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Neurophysiology 

Neurophysiology
Chapter:
Neurophysiology
Author(s):

Eduardo E. Benarroch

, Jeremy K. Cutsforth-Gregory

, and Kelly D. Flemming

DOI:
10.1093/med/9780190209407.003.0005
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Objectives

  1. 1. Describe the structure of the cell membrane and ion channels.

  2. 2. Name the variables that determine the membrane potential.

  3. 3. Define equilibrium potential.

  4. 4. Describe the effects of increased permeability to sodium, potassium, calcium, and chloride ions on the membrane potential and cell excitability.

  5. 5. Describe the mechanisms by which the resting potential is generated.

  6. 6. List the characteristics of a local potential, and name 3 examples.

  7. 7. Describe the features of an action potential and the associated ionic changes.

  8. 8. Define threshold, afterpotential, accommodation, and refractory period.

  9. 9. Describe the effects of the myelin sheath on conduction of the action potential.

  10. 10. Define excitatory and inhibitory postsynaptic potentials, and describe their ionic basis.

  11. 11. Define spatial summation, temporal summation, and presynaptic inhibition.

  12. 12. Describe the effect of anoxia and other causes of energy failure on membrane potential and neuronal excitability.

  13. 13. List several ion channel disorders and their clinical manifestations.

Introduction

Knowing the location and function of the structural components of the nervous system, as presented in Chapter 3 (“Anatomical Localization”), permits localization of the site of a lesion. The temporal profile of the major types of disease, as presented in Chapter 4 (“Neurocytology and Pathologic Reactions of the Nervous System”), assists in identifying the cause of the disorder. However, the temporal profile that has not yet been considered is the transient, or rapidly reversible, abnormality. Many diseases that produce signs or symptoms of brief duration may not produce destructive changes in cells and may occur without demonstrable histologic abnormality of the involved structures. To understand transient manifestations of disease, it is necessary to understand the physiology of the cells of the nervous system and the mechanism by which they process information. Cells in the nervous system and muscle communicate by electrical signals. Neurons have the ability to generate, conduct, transmit, and respond to electrical activity. Information is transmitted between cells by neurochemical agents that convey the signals from cell to cell. Information is integrated by the interaction of electrical activity in single cells and in groups of cells.

Although this chapter discusses only the physiology of single cells, it must be remembered that the activity of the central and peripheral nervous systems never depends on the activity of a single neuron or axon but is always mediated by a group of cells or nerve fibers. Information is represented in the nervous system by a change in activity in a group of cells or fibers as they respond to a change in input. The interactions of neurons in large groups are considered in other sections. Transient alterations in the electrophysiology of neurons or muscle cells cause transient symptoms and signs. This chapter provides an introduction to the physiology of neurons, axons, and muscle fibers, which is the basis for information transmission in the central and peripheral neural structures and for the transient symptoms and signs that accompany disease states.

Overview

The major functions of the nervous system are transmission, storage, and processing of information. These functions are accomplished by the generation, conduction, and integration of electrical activity and by the synthesis and release of chemical agents. The electrical activity in neurons and muscle cells is manifested as electrical potentials called membrane potentials. The membrane potential is the difference in electrical potential between the inside and outside of a cell. All neurons (including their cell bodies, dendrites, and axons), glial cells and muscle cells have a membrane potential. All membrane potentials result from the flow of ions through channels in the membrane. The ions involved include potassium (K+), sodium (Na+), calcium (Ca2+), and chloride (Cl). Membrane potentials include the resting membrane potential, local potentials, and the action potential (Table 5.1). These membrane potentials are determined by the interaction of 2 independent variables: 1) the concentration gradient of each of these ions across the membrane and 2) the permeability of the membrane to each of these ions (Figure 5.1).

Table 5.1 Types of Membrane Potentials

Feature

Resting Membrane Potential

Local Potentials

Action Potential

Response to stimulus

Steady-state potential in the absence of stimulus

Graded (proportional to intensity of stimulus)

All-or-none

Amplitude

May show spontaneous fluctuations below threshold

Decremental (decreases in time and space according to the cable properties of the membrane)

Nondecremental

Propagation

None

Remains localized to a restricted portion of the membrane

Propagates at a distance

Ion channel involved

Primarily leak K+ channels

  • Voltage- or neurotransmitter-gated Na+, K+, Ca2+, and Cl channels

  • Cable properties of the membrane (electrotonic potentialsa)

Primarily voltage-gated Na+ and K+ channels; sometimes Ca2+ channels and other K+ channels

Function

Membrane excitability

  • Sensory transduction (receptor potential)

  • Neurotransmitter effect (synaptic potential)

  • Passive propagation of other potentials (electrotonic potentialsa)

  • Conduction of electrical signals at a distance along axons

  • Coding of information in the nervous system

  • Triggering of exocytosis at the presynaptic terminal

Abbreviations: Ca2+, calcium; Cl, chloride; K+, potassium; Na+, sodium.

a Electrotonic potentials are passive local changes in current flow and do not involve ion channels directly.

Figure 5.1 Variables That Determine the Equilibrium Potential of a Particular Ion. Transmembrane gradients depend on the activity of adenosine triphosphate (ATP)-driven ion pumps and the buffering effects of the astrocytes on the composition of extracellular fluid. Membrane permeability to a particular ion depends on the opening of specific ion channels. This opening can be triggered by voltage (voltage-gated channels), neurotransmitters (ligand-gated channels), or intracellular chemicals such as calcium, ATP, or cyclic nucleotides (chemically gated channels). Increased membrane permeability to a given ion (the opening of an ion channel) brings the membrane potential toward the equilibrium potential of that ion. ATPase indicates adenosine triphosphatase; K+, potassium; Na+, sodium.

Figure 5.1 Variables That Determine the Equilibrium Potential of a Particular Ion. Transmembrane gradients depend on the activity of adenosine triphosphate (ATP)-driven ion pumps and the buffering effects of the astrocytes on the composition of extracellular fluid. Membrane permeability to a particular ion depends on the opening of specific ion channels. This opening can be triggered by voltage (voltage-gated channels), neurotransmitters (ligand-gated channels), or intracellular chemicals such as calcium, ATP, or cyclic nucleotides (chemically gated channels). Increased membrane permeability to a given ion (the opening of an ion channel) brings the membrane potential toward the equilibrium potential of that ion. ATPase indicates adenosine triphosphatase; K+, potassium; Na+, sodium.

The concentrations of Na+, Ca2+, and Cl are higher extracellularly, and those of K+ and impermeable anions are higher intracellularly. With these concentration differences, ions tend to move across the membrane and thereby generate a change in electrical potential—called equilibrium potential—across the membrane. The equilibrium potential varies for each ion according to its concentration gradient. The equilibrium potential of a given ion is the voltage difference across the membrane that exactly offsets the tendency of the ion to move down its concentration gradient. These transmembrane concentration gradients are both maintained and actively restored after neuronal activity by active transport of these ions across the membrane against their concentration gradient; this involves adenosine triphosphate (ATP)-dependent ion pumps, primarily Na+,K+–adenosine triphosphatase (ATPase). The second variable determining the membrane potential is the passive movement of ions across the cell membrane through ion channels. Ion channels are transmembrane proteins that provide aqueous pores to allow the movement of ions according to the transmembrane concentration gradient. The ability of each ion to move across the cell membrane depends on the permeability (or open probability) of the respective ion channel at a given time.

Except for some K+ channels that are open at rest, most ion channels open (or in some cases, close) in response to specific stimuli. These stimuli include changes in membrane potential (voltage-gated ion channels), binding of a neurotransmitter to a postsynaptic receptor (ligand-gated channels), chemical changes in the cytoplasm (chemical-gated ion channels), or activation of a sensory receptor cell. The opening (increased permeability) of a channel for a particular ion shifts the membrane potential toward the equilibrium potential of that ion. Thus, the influence of a particular ion on the membrane potential depends on how permeable the membrane is to that ion.

The resting membrane potential is the membrane potential when the cell is not processing incoming information. In many neurons, the resting membrane potential shows spontaneous fluctuations that determine its responsiveness to incoming inputs. The resting membrane potential depends primarily on the transmembrane concentration and resting permeability of K+ and the activity of the ATP-dependent Na+-K+ pump. In response to a stimulus, a local change occurs in the membrane potential, called a local potential (Figure 5.2). This can be triggered by a sensory stimulus acting on a sensory receptor (receptor potential or generator potential), a neurotransmitter acting on a postsynaptic receptor (synaptic potential), or a local electrical current (electrotonic potential). The amplitude of these local potentials, which is proportional to the intensity of the triggering stimulus, decreases in time and space. Generator potentials triggered by sensory stimuli and excitatory postsynaptic potentials reflect local opening of Na+ or sometimes Ca2+ channels, shifting the membrane potential toward the equilibrium potential of these ions. The membrane thus becomes electropositive with respect to its resting value, referred to as depolarization.

Figure 5.2 Local Potentials and Triggering of the Action Potential. Three types of local potentials are 1) receptor (or generator) potential, triggered by the action of a sensory stimulus on a sensory receptor; 2) synaptic potential, triggered by the action of a neurotransmitter; and 3) electrotonic potential, which consists of the passive movement of charges according to the cable properties of a membrane. Both generator and synaptic potentials give rise to electrotonic potentials, which depolarize the membrane to the threshold for triggering an action potential. The action potential is a regenerating depolarizing stimulus that, through electrotonic potentials, propagates over a distance without decrement of its amplitude.

Figure 5.2 Local Potentials and Triggering of the Action Potential. Three types of local potentials are 1) receptor (or generator) potential, triggered by the action of a sensory stimulus on a sensory receptor; 2) synaptic potential, triggered by the action of a neurotransmitter; and 3) electrotonic potential, which consists of the passive movement of charges according to the cable properties of a membrane. Both generator and synaptic potentials give rise to electrotonic potentials, which depolarize the membrane to the threshold for triggering an action potential. The action potential is a regenerating depolarizing stimulus that, through electrotonic potentials, propagates over a distance without decrement of its amplitude.

When the membrane becomes electropositive (about 10–20 mV) from rest, voltage-gated Na+ channels open abruptly, leading to massive Na+ influx and generation of an action potential (or spike). The receptor potential, synaptic potential, and action potentials generate local electrotonic potentials that depolarize the adjacent membrane.

The ability of a neuron or muscle cell to generate an action potential is called excitability, which depends on the ability of the membrane to reach a threshold to open the voltage-gated Na+ channel. In neurons, the axon initial segment contains the highest concentration of voltage-gated Na+ channels and therefore the lowest threshold; it is thus the site of initiation of the action potential. Unlike local potentials, an action potential is an all-or-none event and propagates without decrement along the axon (Table 5.1). The conduction velocity of the action potential is proportional to the diameter of the axon and is mainly determined by the presence of a myelin sheath, which serves as an insulator and allows the clustering of voltage-gated Na+ channels at specific sites called nodes of Ranvier.

On reaching the presynaptic axon terminal, the action potential elicits a membrane depolarization that results in the opening of voltage-gated Ca2+ channels. The influx of Ca2+ into the presynaptic terminal triggers the release of a neurotransmitter by exocytosis. This neurotransmitter binds to a receptor molecule in the postsynaptic cell membrane, triggering a local potential (synaptic potential) that, according to the type of neurotransmitter and receptor, may increase or decrease the excitability of the postsynaptic neuron by eliciting depolarization or hyperpolarization of its membrane.

By acting on different specific receptors, neurotransmitters may evoke 2 types of postsynaptic effects, referred to as classical neurotransmission and neuromodulation. Classical neurotransmission depends on the opening of specific neurotransmitter (ligand)-gated ion channels and results in fast excitatory (if Na+ or Ca2+ channels open) or inhibitory (if Cl channels open) postsynaptic potentials. Neuromodulation affects the probability of the cell releasing a neurotransmitter (presynaptic modulation) or responding to other neurotransmitters (postsynaptic modulation) by affecting voltage-gated Ca2+ or K+ channels. Neuromodulation is primarily mediated by G protein–coupled receptors that control voltage-gated K+ or Ca2+ channels.

The synaptic information is integrated in neurons by the interaction of local potentials generated in response to the different neurotransmitters that act on the cell. In the nervous system, information can be coded either as the rate of discharge in individual cells or their axons or as the number and combination of active cells. The combined activity of a large number of cells (neuronal networks) determines the behavior of the organism.

Transient neurologic disorders reflect the reversible disturbance of neuronal excitability and synaptic interactions affecting neuronal networks. These abnormalities may be due to the failure of ion pumps to maintain electrochemical gradients (as in disorders associated with failure to generate ATP, such as hypoxia-ischemia or hypoglycemia), impaired function of ion channels due to genetic or autoimmune disorders (channelopathies), toxins, pharmacologic blockade, or alterations in the ionic composition of the extracellular fluid.

These disorders affect the ability to initiate or propagate action potentials or communicate by chemical synapses. Transient disorders may be generalized or focal and be manifested by excessive activity (eg, seizures) or decreased activity (eg, loss of sensation, weakness, or reduced consciousness) or both. Transient disorders do not permit a pathologic or etiologic diagnosis. Any type of disease (vascular, neoplastic, inflammatory, or genetic) may be associated with transient changes. Therefore, the pathologic mechanism of a disorder cannot be deduced when its temporal profile is solely that of transient episodes.

Plasma Membrane

Organization of the Plasma Membrane

Structure

The plasma membrane is a lipid bilayer composed primarily of phospholipids, with the polar (hydrophilic) heads facing outward and the nonpolar (hydrophobic) tails extending to the middle of the bilayer. The lipid bilayer is relatively impermeable to water-soluble molecules, including ions such as Na+, K+, Cl, and Ca2+. Embedded in this lipid bilayer are protein macromolecules, including ion channels, receptors, and ionic pumps, that are in contact with both the extracellular fluid and the cytoplasm.

The distribution of ion channels and other transmembrane proteins varies among the components of the neurons (dendrites, cell bodies, and different portions of the axon). This differential distribution of ion channels, transporters, and receptors in the compartments of the cell membrane is critical for neuronal function (Additional Information 5.1).

Transmembrane Ion Flow

Transmembrane proteins allow the passive or active passage of ions across the membrane, which is critical for the electrophysiologic behavior of the cell. Ion channels, ion pumps, and transporters are membrane proteins with multiple transmembrane domains. The concentrations of Na+, Cl, and Ca2+ are higher extracellularly, and the concentrations of K+ and impermeable anions are higher intracellularly (Figure 5.3; Table 5.2).

Figure 5.3 Transmembrane Ion Concentrations, Equilibrium Potential, and Resting Membrane Potential (Vm). The semipermeable cell membrane determines a differential distribution of ions in the intracellular and extracellular compartments. Sodium (Na+) and chloride (Cl–) ions predominate extracellularly, and potassium (K+) and nondiffusible (A–) ions predominate intracellularly. The transmembrane ion composition is maintained by the activity of adenosine triphosphate–dependent pumps, particularly Na+,K+-adenosine triphosphatase (ATPase). The different transmembrane concentrations of diffusible ions determine the equilibrium potential (E) of each ion. The contribution of each ion to the Vm depends on the permeability of the membrane to that particular ion. Increased permeability to an ion brings the Vm toward the E of that ion. At rest, the membrane is predominantly, but not exclusively, permeable to K+. Ca2+ indicates calcium.

Figure 5.3 Transmembrane Ion Concentrations, Equilibrium Potential, and Resting Membrane Potential (Vm). The semipermeable cell membrane determines a differential distribution of ions in the intracellular and extracellular compartments. Sodium (Na+) and chloride (Cl) ions predominate extracellularly, and potassium (K+) and nondiffusible (A) ions predominate intracellularly. The transmembrane ion composition is maintained by the activity of adenosine triphosphate–dependent pumps, particularly Na+,K+-adenosine triphosphatase (ATPase). The different transmembrane concentrations of diffusible ions determine the equilibrium potential (E) of each ion. The contribution of each ion to the Vm depends on the permeability of the membrane to that particular ion. Increased permeability to an ion brings the Vm toward the E of that ion. At rest, the membrane is predominantly, but not exclusively, permeable to K+. Ca2+ indicates calcium.

Table 5.2 Relative Ion Concentrations, Equilibrium Potential, and Resting Permeability

Feature

K+

Na+

Cl

Ca2+

Internal concentration

High

Low

Low (in adult neurons)

Low

External concentration

Low

High

High (in adult neurons)

High

Equilibrium potential, mV

–100

+40

–75 (in adult neurons)

>120

Resting permeability

High

Low

High

Very low

Relevance to the resting membrane potential

Main determinant

Slight depolarizing influence

  • Minimal in neurons

  • Important in skeletal muscle

Maintains its stability

Abbreviations: Ca2+, calcium; Cl, chloride; K+, potassium; Na+, sodium.

The transmembrane ion concentration and ion flow across the ion channels determine the membrane potential. Thus, the membrane potential primarily depends on the balance between 1) the passive diffusion of ions across ion channels (pores) of the membrane and 2) active, energy-dependent transport of ions against their concentration gradient by ATP-driven ion pumps.

Ion Channels

General Features

Ion channels are intrinsic membrane proteins that form hydrophilic pores (aqueous pathways) through the lipid bilayer membrane. They allow the passive flow of selected ions across the membrane on the basis of the electrochemical gradients of the ion and the physical properties of the ion channel. Most channels belong to 1 of several superfamilies of homologous multimeric proteins composed of subunits with several transmembrane domains. Ion channels vary in their 1) selectivity for specific ions, 2) trigger for channel opening (gating), 3) permeability (electrical conductance), 4) kinetics of channel opening (activation) and closing (inactivation), and 5) sensitivity to drugs or toxins. These properties are determined by several variables, including the subunit composition of the channels, state of phosphorylation of the ion channel subunits, interactions with auxiliary proteins, and allosteric modulators (Figure 5.4).

Figure 5.4 General Features of Ion Channels. Ion channels vary in their selectivity for specific ions, triggers for channel opening (gating), kinetics of channel opening (activation) and closing (inactivation), and sensitivity to drugs or toxins. These properties are determined by the subunit composition of the channels, state of phosphorylation of the ion channel subunits, interactions with auxiliary proteins, and allosteric modulators. Ca2+ indicates calcium; Cl–, chloride; K+, potassium; Mg2+, magnesium; Na+, sodium; Zn2+, zinc.

Figure 5.4 General Features of Ion Channels. Ion channels vary in their selectivity for specific ions, triggers for channel opening (gating), kinetics of channel opening (activation) and closing (inactivation), and sensitivity to drugs or toxins. These properties are determined by the subunit composition of the channels, state of phosphorylation of the ion channel subunits, interactions with auxiliary proteins, and allosteric modulators. Ca2+ indicates calcium; Cl, chloride; K+, potassium; Mg2+, magnesium; Na+, sodium; Zn2+, zinc.

Some ion channels are permeable to cations (Na+, K+, and Ca2+) and others to anions (primarily Cl). Whereas a few ion channels are open at the resting state (eg, K+ channels responsible for the resting membrane potential), most are gated; that is, they open in response to specific stimuli. According to their gating stimuli, ion channels can be subdivided into 1) voltage-gated channels, which respond to changes in membrane potential; 2) ligand-gated channels, which respond to the binding of a neurotransmitter to the channel molecular complex; 3) chemically gated channels, which respond to intracellular molecules such as ATP, ions (particularly Ca2+), and cyclic nucleotides; and 4) other channels that are gated by mechanical, thermal, or chemical stimuli. The basic electrophysiologic behaviors of neurons depend on voltage-gated and neurotransmitter (ligand)-gated channels. These channels are differentially distributed in the compartments of the neuron, where they have specific functions (Table 5.3).

Table 5.3 Localization and Function of Voltage-Gated and Ligand-Gated Channels

Ion Channel

Main Location

Function

  • Voltage-gated

  • Na+

  • Axon initial segment

  • Node of Ranvier

  • Dendrites

  • Initiation of the action potential

  • Conduction of the action potential

  • Boosting of postsynaptic potentials

K+

Diffuse but variable throughout the neuron

  • Decrease neuronal excitability

  • Repolarization of the action potential

  • Decrease rate of firing of action potentials

Ca2+

  • Dendrites (and soma)

  • Presynaptic terminal

  • Slow depolarization (L channels)

  • Rhythmic burst firing (T channels)

  • Neurotransmitter release (P/Q and N channels)

  • Neurotransmitter-gated

  • Nicotinic acetylcholine receptor (Na+ and Ca2+)

  • Motor end plate

  • Dendrites

  • Presynaptic terminals

  • Fast excitation

  • Neurotransmitter release

Ionotropic glutamate receptor (Na+ and Ca2+)

Dendritic spines and dendrites of CNS neurons

Fast excitation

GABAA receptor (Cl)

  • Dendritic shafts

  • Soma

  • Axon initial segment

  • Presynaptic terminal

Fast inhibition

Glycine receptor (Cl)

  • Dendritic shafts

  • Soma

Fast inhibition

Abbreviations: Ca2+, calcium; Cl, chloride; CNS, central nervous system; GABAA, γ‎-aminobutyric acid A; K+, potassium; Na+, sodium.

Voltage-Gated Channels

Voltage-gated ion channels are critical for several electrophysiologic properties of neurons and muscle cells. These channels are typically activated when the membrane potential becomes electropositive from the resting potential (depolarization). Voltage-gated cation channels are part of a superfamily of proteins that share a basic structure, including a principal or α‎-subunit and a variable number of accessory subunits. The principal subunit contains the voltage sensor and a pore domain (Figure 5.5). The amino acid composition of this subunit determines its ion selectivity and mediates the voltage sensing of the channel; it is sufficient for the function of the channel (Additional Information 5.2).

Figure 5.5 General Structure of Voltage-Gated Cation Channels. Voltage-gated cation channels are part of a superfamily of proteins with a common basic structure consisting of pore-forming subunits, generally referred to as α‎-subunits, and a variable number of accessory subunits. Voltage-gated K+ channels are made up of 4 homologous α‎-subunits. The α‎-subunits of voltage-gated Na+ and Ca2+ channels contain 4 highly homologous domains, with each resembling the elementary α‎-subunits of voltage-gated K+ channels. S1 through S6 indicate transmembrane segments.

Figure 5.5 General Structure of Voltage-Gated Cation Channels. Voltage-gated cation channels are part of a superfamily of proteins with a common basic structure consisting of pore-forming subunits, generally referred to as α‎-subunits, and a variable number of accessory subunits. Voltage-gated K+ channels are made up of 4 homologous α‎-subunits. The α‎-subunits of voltage-gated Na+ and Ca2+ channels contain 4 highly homologous domains, with each resembling the elementary α‎-subunits of voltage-gated K+ channels. S1 through S6 indicate transmembrane segments.

(Adapted from Benarroch EE. Basic neurosciences with clinical applications. Philadelphia (PA): Butterworth Heinemann/Elsevier; c2006. Chapter 7, Ion channels and channelopathies; p. 173–211. Used with permission of Mayo Foundation for Medical Education and Research.)

Voltage-gated Na+ channels are involved in the generation and conduction of the action potential (nerve impulse) in neurons and muscle cells. In neurons, Na+ channels are concentrated in the initial segment of the axon (the site of generation of action potentials) and in the nodes of Ranvier (involved in rapid conduction of action potentials).

There are several types of voltage-gated Ca2+ channels. Those located in the soma and dendrites, including the dendritic spines, are important for boosting synaptic signals, while others mediate slow action potentials that are necessary for the rhythmic firing of some neurons. The influx of Ca2+ through voltage-gated channels located in presynaptic terminals is critical for the release of neurotransmitters.

There are many types of K+ channels, which are responsible for creating the resting membrane potential, repolarizing the action potential, and controlling the probability of generating repetitive action potentials. Some are open at rest (“leak” channels); others are gated by voltage (voltage-gated K+ channels), by an increase in intracellular Ca2+ (Ca2+-activated K+ channels), or by other intracellular signals such as ATP.

Neurotransmitter (Ligand)-Gated Channels

Ligand-gated channels open in response to the binding of neurotransmitters (Figure 5.6). They include cation channels permeable to Na+ or Ca2+ (or both) and anion channels permeable to Cl. These channels are primarily distributed to the dendrites (including dendritic shafts and dendritic spines) and soma and, in some cases, presynaptic terminals. Neurotransmitter-gated cation channels elicit fast excitatory postsynaptic potentials, whereas Cl channels elicit fast inhibitory potentials. These channels are discussed in relation to synaptic transmission later in this chapter and in Chapter 6 (“Neurochemistry”) (Additional Information 5.3) (Figure 5.6).

Figure 5.6 Ligand-Gated Channels. When a neurotransmitter (eg, glutamate) binds to a specific ligand-gated cation channel, the spatial configuration of the channel protein changes, allowing the pore to open and the cation to pass through the membrane. Changes in the amino acid composition of the ion channel protein affect its ion selectivity and gating mechanism as well as the kinetics of channel opening (activation) and closing (inactivation).

Figure 5.6 Ligand-Gated Channels. When a neurotransmitter (eg, glutamate) binds to a specific ligand-gated cation channel, the spatial configuration of the channel protein changes, allowing the pore to open and the cation to pass through the membrane. Changes in the amino acid composition of the ion channel protein affect its ion selectivity and gating mechanism as well as the kinetics of channel opening (activation) and closing (inactivation).

Ion Pumps and Transporters

Ion Pumps

Ion pumps are transmembrane proteins that, unlike ion channels, transport ions across the membrane against their concentration gradient, with the consumption of ATP. Active ion transport by ion pumps is critical for maintenance of the transmembrane ion concentration gradient. For example, there is continuous leakage of K+ out of the cell and of Na+ into the cell, driven by both the concentration and the electrical gradients. The ion gradient is restored by the activity of Na+,K+-ATPase. In nerve cells, glial cells, and muscle cells, the main source of ATP is the oxidative metabolism of glucose (aerobic glycolysis) involving the Krebs cycle and respiratory chain in mitochondria. The main consumption of ATP in the nervous system is to fuel Na+,K+-ATPase. Calcium ATPases, located in the plasma membrane and endoplasmic reticulum, are important for maintaining the cytosolic levels of Ca2+ within a narrow range.

Transporters

The transmembrane Na+ gradients maintained by the activity of Na+,K+-ATPase drive several Na+-dependent neuronal and astroglial pumps and transporters that are critical for neuronal function and survival. These include ion pumps and transporters involved in control of cell volume and pH, those involved in reuptake of synaptically released neurotransmitters, and those required for uptake of nutrients such as glucose, amino acids, and lactate.

One important concept is that, unlike ion channels, ion pumps and transporters are impaired in conditions associated with energy failure, such as hypoxia, because they impair mitochondrial oxidative metabolism and ATP production. Lack of ATP impairs activity of Na+,K+-ATPase and maintenance of transmembrane Na+ gradients, thereby affecting membrane potential, Na+-driven pumps involved in maintaining cell homeostasis, and Na+-dependent transporters.

Cable Properties

The plasma membrane in excitable tissues, such as neuronal dendrites, cell bodies, axons, and different types of muscle, acts as an electrical cable with characteristic resistance and capacitance. These cable properties, also referred to as passive properties, determine the amplitude, duration, and longitudinal spread of electrical currents generated by ion flow through channels, pumps, and transporters (referred to as active properties).

Determinants of the Membrane Potential

The potential across the cell membrane at a given time depends on 2 variables: the transmembrane ion concentration gradient and the permeability of the membrane to each ion (Figure 5.1).

Equilibrium Potential of Individual Ions

The transmembrane ion concentration gradient and charge of each ion determine the equilibrium potential of that ion (Figure 5.3; Table 5.2). The diffusible ions (Na+, K+, and Cl, but not Ca2+) tend to move spontaneously across the cell membrane according to their concentration gradient. The molecular motion of ions is a source of energy known as the diffusion pressure. For example, the intracellular concentration of K+ is 30 times greater than the extracellular concentration; therefore, K+ tends to diffuse from the intracellular to the extracellular space. The opposite occurs with Na+.

As ions diffuse across the cell membrane, a separation of charges develops because the nondiffusible negatively charged intracellular ions (principally proteins) have a charge opposite that of the diffusible ions. Two regions that accumulate different charges have an electrical potential difference. As a diffusible ion moves across the membrane, the developed voltage produces an electrical pressure that opposes the movement of the ion. The net ionic movement continues until the electrical pressure equals the diffusion pressure. At that time, the system is in equilibrium with no net movement of ions across the membrane.

Transmembrane Ion Gradient as the Driver of the Equilibrium Potential

The equilibrium potential of an ion is the voltage difference across the membrane that exactly offsets the diffusion pressure of an ion to move down its concentration gradient. Therefore, the equilibrium potential is proportional to the difference between the concentration of the ion in the extracellular fluid and its concentration in the intracellular fluid (Additional Information 5.4).

Effects of Ion Channel Permeability on the Membrane Potential

The permeability of the membrane to an individual ion at a given time determines the extent to which the equilibrium potential of this ion contributes to the membrane potential at that time. Permeability is the ease with which an ion diffuses across the membrane and reflects the probability that the ion channel that conducts the ion will open. Thus, the contribution of a given ion to the actual voltage developed across the membrane (ie, membrane potential) depends on its concentration gradient (which determines its equilibrium potential) and on the permeability of the membrane (opening of the ion channel) to that ion (Additional Information 5.5).

Thus, changes in either ionic permeability or ionic concentration can alter membrane potential. An important corollary is that the opening of a channel (an increase in membrane permeability) for a particular ion moves the membrane potential toward the equilibrium potential of that ion. In contrast, the closing of an ion channel moves the membrane potential away from the equilibrium potential of that ion. For example, the high permeability of K+ at rest determines that this ion contributes significantly to the resting potential. In contrast, the opening of a voltage-gated Na+ channel brings the membrane potential toward the equilibrium potential of Na+, triggering an action potential.

Resting Membrane Potential

The resting potential is the absolute difference in electrical potential between the inside and outside of a neuron, axon, or muscle cell in the absence of stimuli. Its value determines spontaneous neuronal activity and neuronal activity in response to extrinsic input. The resting membrane potential depends on 2 main factors: 1) the presence of leak ion channels with markedly different permeabilities to K+ and Na+ and 2) the presence of energy-dependent pumps, particularly the Na+-K+ pump.

Steady State

At rest, there is a continuous leak of K+ outward and Na+ inward across the membrane. Cells at rest have a much higher permeability to K+ than to Na+. Potassium diffuses through the membrane most readily because of the presence of leak K+ channels. In the absence of synaptic activity, the membrane potential is dominated by its high permeability to K+, and the membrane potential is thus drawn toward the equilibrium potential of this ion (–100 mV). Because the membrane at rest is also permeable to Na+, however, the membrane potential is pulled slightly toward the equilibrium potential of this ion. Although the resting potential varies among different types of neurons, it is typically –60 to –80 mV.

Because small amounts of Na+ are driven into the cell by both electrical and chemical forces and because the membrane potential is not equal to the equilibrium potential of K+, K+ flows out of the cell. This small outward K+ leak must be exactly equal in magnitude to the rate at which K+ is transported into the cell. The same is true also for Na+. Thus, the cell is not in equilibrium but rather in a steady state, in which the net movement of each ion across the membrane is zero.

The cell membrane at rest is permeable also to Cl ions. In most membranes, Cl reaches equilibrium simply by adjustment of its internal concentration, which maintains electroneutrality, without affecting the steady-state membrane potential.

Na+, K+-ATPase

The Na+-K+ pump (Na+,K+-ATPase) maintains the intracellular concentrations of Na+ and K+ ions despite their constant leakage through the membrane. The Na+-K+ pump transports 3 Na+ ions out of the cell for every 2 K+ ions carried into the cell. Because the pump is not electrically neutral, it also contributes directly to the resting potential; that is, it is electrogenic. The contribution of the Na+-K+ pump at steady state to the resting potential is approximately –11 mV. Failure of Na+,K+-ATPase leads to an inability to pump Na+ out of cells and K+ into cells; as a result, the leak flow of these ions down their concentration gradients continues unopposed.

In a normal nerve or muscle cell with adequate sources of oxygen and glucose, the resting potential is maintained at a relatively stable level. However, neurons are continuously exposed to a wide range of synaptic influences that trigger ion flows and thereby produce spontaneous fluctuations of the resting potential.

Ionic Basis of Membrane Depolarization and Hyperpolarization

The membrane potential changes readily in response to stimuli. A decrease in the membrane potential toward a less negative value than the resting membrane potential (ie, toward zero) constitutes depolarization. Hyperpolarization occurs when the membrane potential becomes more negative than the value of the resting potential. In physiologic conditions, changes in the membrane potential are rapid and transient (in milliseconds to seconds). They occur in response to electrical, mechanical, or chemical stimuli that produce transient activation or inactivation of ion channels, resulting in current flow through the membrane (Figure 5.7).

Figure 5.7 Ionic Basis of Depolarization and Hyperpolarization. Transient opening of sodium (Na+) or calcium (Ca2+) channels elicits an inward current that results in depolarization as the membrane potential moves toward the equilibrium potential (E) of the ion (which is positive with respect to the resting membrane potential [RMP]). Depolarization in neurons may also occur in response to closure of potassium (K+) channels, which causes the membrane potential to move away from EK+ (which is electronegative with respect to RMP). In contrast, opening of K+ channels leads to hyperpolarization. Since the E of chloride (Cl–) (ECl–) is close to the RMP, opening of Cl– channels may elicit membrane depolarization, hyperpolarization, or essentially no change, depending on the transmembrane Cl– concentration gradient.

Figure 5.7 Ionic Basis of Depolarization and Hyperpolarization. Transient opening of sodium (Na+) or calcium (Ca2+) channels elicits an inward current that results in depolarization as the membrane potential moves toward the equilibrium potential (E) of the ion (which is positive with respect to the resting membrane potential [RMP]). Depolarization in neurons may also occur in response to closure of potassium (K+) channels, which causes the membrane potential to move away from EK+ (which is electronegative with respect to RMP). In contrast, opening of K+ channels leads to hyperpolarization. Since the E of chloride (Cl) (ECl) is close to the RMP, opening of Cl channels may elicit membrane depolarization, hyperpolarization, or essentially no change, depending on the transmembrane Cl concentration gradient.

Transient opening of Na+ or Ca2+ channels elicits an inward current that results in depolarization as the membrane potential moves toward the equilibrium potentials of these ions (which are positive with respect to the resting membrane potential). Depolarization in neurons may also occur in response to closure of K+ channels, which causes the membrane potential to move away from the equilibrium potential of K+ (which is electronegative with respect to the resting membrane potential). In contrast, opening of K+ channels leads to hyperpolarization by promoting outward flow of this cation from the cell. Since the equilibrium potential of Cl is close to the resting membrane potential, opening of Cl channels may elicit membrane depolarization, hyperpolarization, or essentially no change, depending on the transmembrane Cl concentration gradient.

Membrane Excitability

The excitability of a neuron, axon, or muscle cell is defined as the probability of generating or transmitting an action potential.

Mechanisms

Because triggering of an action potential depends on the opening of a voltage-gated Na+ channel, the membrane potential needs to reach a value that activates (gates) the channel. This is called threshold. For a neuron with a resting membrane potential of –60 to –80 mV, the threshold for opening of voltage-gated Na+ channels is approximately 10 to 15 mV positive from the resting potential (approximately –55 mV). Therefore, influences that depolarize the membrane toward threshold make the neuron more excitable, whereas influences that hyperpolarize the membrane make the cell less excitable (Figure 5.8).

Figure 5.8 Membrane Conductance. Changes in membrane conductance (g) resulting in depolarization or hyperpolarization affect the probability of the neuron reaching threshold to trigger an action potential (neuronal excitability). Ca2+ indicates calcium; Cl–, chloride; E, equilibrium potential; K+, potassium; Na+, sodium; RMP, resting membrane potential.

Figure 5.8 Membrane Conductance. Changes in membrane conductance (g) resulting in depolarization or hyperpolarization affect the probability of the neuron reaching threshold to trigger an action potential (neuronal excitability). Ca2+ indicates calcium; Cl, chloride; E, equilibrium potential; K+, potassium; Na+, sodium; RMP, resting membrane potential.

(Adapted from Benarroch EE. Basic neurosciences with clinical applications. Philadelphia (PA): Butterworth Heinemann/Elsevier; c2006. Chapter 7, Ion channels and channelopathies; p. 173–211. Used with permission of Mayo Foundation for Medical Education and Research.)

Depolarization Block

Because the voltage-gated Na+ channel closes (inactivates) rapidly at membrane potentials more positive than threshold, the membrane must return to its resting value (repolarize) before the channel can be activated again. Thus, whereas small membrane depolarization toward threshold increases neuronal (or muscle cell) excitability, a large depolarization above threshold renders the cell inexcitable because of inactivation of voltage-gated Na+ channels. This is referred to as depolarization block. Neuronal, axonal, or muscle inexcitability due to this mechanism may occur in 3 pathologic settings: 1) energy failure producing impairment of Na+,K+-ATPase, 2) changes in transmembrane concentrations of K+, and 3) genetic or acquired disorders that affect the kinetics of activation (opening) or inactivation (closing) of channels. In these conditions, initial membrane depolarization may result in a transient increase in excitability (by moving the membrane potential toward threshold), but if the depolarization is more marked and persistent, it renders the cell inexcitable due to inactivation of voltage-gated Na+ channels.

Role of Extracellular Calcium

The external surface of the cell membrane contains a high density of negative charges because of the presence of glycoprotein residues in membrane proteins. This produces a negative potential difference that contributes to the resting membrane potential. By binding to the negative charges of the surface membrane, extracellular Ca2+ neutralizes this negative surface potential. This increases the contribution of the transmembrane potential to the resting potential and thus increases the threshold for opening of the voltage-gated Na+ channels. This explains the stabilizing effect of extracellular Ca2+ on membrane excitability and the increased spontaneous activity (tetany) that occurs in patients with hypocalcemia or alkalosis.

Role of Glial Cells

Astrocytes are important in controlling the extracellular concentration of K+. Astrocytes are highly permeable to K+ and are interconnected by gap junctions. When the extracellular concentration of K+ increases secondary to neuronal activity, astrocytes incorporate K+ and transfer it from cell to cell through gap junctions. This spatial buffering of extracellular K+ prevents the extracellular accumulation of K+ and maintains neuronal excitability.

Local Potentials

A local potential is a transient depolarizing or hyperpolarizing shift of the membrane potential in a localized area of the cell. Local potentials result from current flow due to localized change in ion channel permeability to 1 or more ions. Ion channel opening or closing may result from 1) activation of a sensory receptor channel by a stimulus (a receptor potential), 2) a chemical neurotransmitter released at the level of the synapse (a synaptic potential), or 3) current from an externally applied voltage (an electrotonic potential) (Table 5.4).

Table 5.4 Types of Local Potentials

Type of Potential

Location

Ionic Basis

Effect

Receptor (generator)

Sensory receptors

Opening of Na+ (sometimes Ca2+) channels

Depolarization (transduction of the sensory input)

Fast excitatory postsynaptic

Postsynaptic membrane (primarily dendrites)

Opening of Na+ or Ca2+ channels (or both)

Fast depolarization (synaptic excitation)

Fast inhibitory postsynaptic

Postsynaptic membrane (primarily dendrites)

Opening of Cl channels

Fast inhibition (most adult neurons)

Slow excitatory postsynaptic

Postsynaptic membrane (primarily dendrites)

Closing of K+ channels

Slow depolarization and increase excitability

Slow inhibitory postsynaptic

Postsynaptic membrane (primarily dendrites)

Opening of K+ channels

Slow hyperpolarization and decrease excitability

Electrotonic

Elicited at the sites of depolarization in sensory receptors, synaptic receptors, or axons

None (electrical current)

Depolarization of neighboring membrane

Abbreviations: Ca2+, calcium; Cl, chloride; K+, potassium; Na+, sodium.

Ionic Basis

Receptor (Generator) Potentials

Stimulation of sensory receptors, including mechanoreceptors (such as those involved in the sensation of touch or hearing) and receptors involved in the sensations of pain, temperature, smell, and taste, results in the opening of a cation channel and membrane depolarization. The exception is the case of photoreceptors, in which light triggers a biochemical cascade that results in the closing of a cation channel that is open during darkness. Thus, with the exception of photoreceptors, receptor (generator) potentials are depolarizing, leading to the triggering of action potentials.

Synaptic Potentials

Synaptically released neurotransmitters elicit local changes in membrane potential by 2 main mechanisms mediated by 2 types of neurotransmitter receptors. When a neurotransmitter binds to a ligand-gated ion channel receptor, it increases the permeability of the ion channel. Neurotransmitter binding to a cation channel receptor leads to increased permeability to Na+ or Ca2+, eliciting depolarization (fast excitatory postsynaptic potential). In contrast, neurotransmitters that bind to a Cl channel receptor elicit fast inhibitory postsynaptic potentials. Neurotransmitters may also increase or decrease the permeability to K+ channels. Accordingly, they may elicit either the opening of K+ channels (leading to hyperpolarization of the membrane and decreased cell excitability) or the closing of K+ channels (leading to membrane depolarization and increased cell excitability).

Electrotonic Potentials

Electrotonic potentials participate in the transfer of electrical information throughout a cell. These potentials reflect the cable (passive) properties of the membrane and are triggered in 1 of 2 ways: 1) the opening of Na+ channels by a current arising from a voltage in an adjacent area of the membrane, producing depolarization, or 2) a negative electrical voltage applied to the external side of the membrane. When voltage is applied to the outside of the axonal membrane, the negative pole is commonly referred to as the cathode and the positive pole is called the anode. The application of a negative voltage to the outside of the membrane causes outward current flow, depolarization of the membrane, and opening of voltage-gated ion channels. In contrast, the anode hyperpolarizes a membrane.

Characteristics of Local Potentials

All local potentials have certain characteristics in common (Table 5.1).

Graded Response and Decrement

The local potential is a graded potential; that is, its amplitude is proportional to the size of the stimulus (Figure 5.9). The change in membrane potential is not instantaneous but develops over a few milliseconds. After the stimulus ends, the potential subsides over a few milliseconds. The amplitude of local potentials decreases with time and with distance from the stimulus. Therefore, when a sensory, synaptic, or electrical stimulus is applied to a localized area of the membrane, the change in membrane potential has both a temporal and a spatial distribution. This reflects the cable properties of the membrane.

Figure 5.9 Local Potentials. Local potentials are shown as an upward deflection if they are depolarizing and as a downward deflection if they are hyperpolarizing. The resting potential is –70 mV in this example. At time zero, electrical currents of various polarities and voltage are applied to the membrane (bottom). An anodal current (A) produces a transient hyperpolarization; cathodal currents (B, C, and D) produce a transient depolarization that is graded and proportional to the size of the stimulus. All these currents are local potentials. Current D depolarizes the membrane to threshold and thus produces an action potential, E.

Figure 5.9 Local Potentials. Local potentials are shown as an upward deflection if they are depolarizing and as a downward deflection if they are hyperpolarizing. The resting potential is –70 mV in this example. At time zero, electrical currents of various polarities and voltage are applied to the membrane (bottom). An anodal current (A) produces a transient hyperpolarization; cathodal currents (B, C, and D) produce a transient depolarization that is graded and proportional to the size of the stimulus. All these currents are local potentials. Current D depolarizes the membrane to threshold and thus produces an action potential, E.

Summation

Because the local potential is a graded response proportional to the size of the stimulus, the occurrence of a second stimulus before the first one subsides will result in a larger local potential. Therefore, local potentials can be summated algebraically, so that similar potentials are additive while hyperpolarizing and depolarizing potentials tend to cancel each other. The summation of local potentials occurring near each other in time is called temporal summation. Through temporal summation, the cell can integrate signals that arrive at different times. Because of local current flow, a locally acting stimulus has an effect on the nearby membrane. Thus, the presence of a simultaneous second stimulus in a site near the first results in summation of the potentials in the border zones (called spatial summation). Spatial and temporal summation are important mechanisms in the processing of information by single neurons. Summated potentials may reach threshold and produce an action potential when single potentials individually are subthreshold (Figure 5.10).

Figure 5.10 Summation of Local Potentials in a Neuron. A, Spatial summation occurs when an increasing number of nerve terminals release more neurotransmitter to produce larger excitatory postsynaptic potentials (EPSPs). B, Temporal summation occurs when a single terminal discharges repetitively and more rapidly to produce larger EPSPs.

Figure 5.10 Summation of Local Potentials in a Neuron. A, Spatial summation occurs when an increasing number of nerve terminals release more neurotransmitter to produce larger excitatory postsynaptic potentials (EPSPs). B, Temporal summation occurs when a single terminal discharges repetitively and more rapidly to produce larger EPSPs.

Accommodation

If a current or voltage is applied to a membrane for more than a few milliseconds, the ion channels revert to their resting state, changing ionic conductances of the membrane in a direction to restore the resting potential to baseline value. This phenomenon is known as accommodation. The changes in conductance during accommodation require several milliseconds, both to develop and to subside. When the stimulus is turned off suddenly, the residual change in conductance produces a transient change in resting potential. Thus, accommodation can result in a cell responding to the cessation of a stimulus.

Action Potential

Action potentials allow the rapid transfer of information in the nervous system. Because action potentials are all-or-none (they either do occur or do not occur), they can transfer information without loss over relatively long distances. The all-or-none feature also allows information to be coded as frequency rather than as amplitude, which is a less stable measure.

Ionic Basis

Voltage-Gated Na+ Channels

If a membrane is depolarized by a sensory, synaptic, or electrical stimulus, the point at which many voltage-gated Na+ channels open suddenly is the threshold for excitation (Figure 5.8). At threshold, opening of voltage-gated Na+ channels elicits an inward current flow that brings the membrane potential toward the equilibrium potential of Na+ (approximately +40 mV), producing a rapid depolarization or spike (Figure 5.11).

Figure 5.11 Conductance Changes During an Action Potential. In this temporal sequence at a single site along an axon, changes in conductances (permeabilities) of sodium (Na+) and potassium (K+) are plotted against time as they change with associated changes in membrane potential. Na+ conductance changes several thousand–fold early in the process, whereas K+ conductance changes only about 30-fold during later stages and persists longer than Na+ conductance changes.

Figure 5.11 Conductance Changes During an Action Potential. In this temporal sequence at a single site along an axon, changes in conductances (permeabilities) of sodium (Na+) and potassium (K+) are plotted against time as they change with associated changes in membrane potential. Na+ conductance changes several thousand–fold early in the process, whereas K+ conductance changes only about 30-fold during later stages and persists longer than Na+ conductance changes.

Most of these channels are fast inactivating voltage-gated Na+ channels; their rapid inactivation after depolarization renders the increase in Na+ conductance transient, lasting only a few milliseconds. These channels are highly concentrated at the axon initial segment, which has the lowest threshold of activation and is typically the site of generation of the action potential. There are also slowly inactivating Na+ channels that contribute to the pattern of firing of the action potential (Additional Information 5.6).

Voltage-Gated K+ Channels

Depolarization triggers the opening of slowly activating voltage-gated K+ channels, leading to an increase in K+ conductance and an outward movement of K+ ions. This repolarization brings the membrane potential back toward the equilibrium potential of K+ (Figure 5.11). Thus, the duration of the action potential depends on the speed of inactivation of the voltage-gated Na+ channel and the increase in K+ conductance of the delayed voltage-gated K+ channel (Additional Information 5.7).

Voltage-Gated Ca2+ Channels

In many neurons, voltage-gated Ca2+ channels contribute to the action potential by several mechanisms. Calcium-mediated action potentials generally are of longer duration and smaller amplitude than typical Na+ potentials. In some cases, the voltage-dependent opening of low-threshold Ca2+ channels (called T-channels) elicits a depolarization that brings the membrane to threshold for opening voltage-gated Na+ channels. In other cases, the depolarization mediated by the Na+-dependent action potential opens high threshold Ca2+ channels (called L-channels). Calcium influx through these channels contributes to membrane repolarization through Ca2+-activated K+channels.

Features of the Action Potential

Interaction of Ion Channels in Shaping the Action Potential

In neurons, and to a lesser extent in axons, the shape of the action potential depends on the interaction of multiple ion channels (Figure 5.12). Whereas fast inactivating voltage-gated Na+ channels are primarily responsible for the depolarization phase or spike, and slowly activating voltage-gated K+ channels are responsible for depolarization of the action potential, other Na+, K+, and Ca2+ channels participate in the shaping and pattern of discharge of the action potential. For example, slowly inactivating Na+ channels produce a small residual component that is positive with respect to the resting potential; this is referred to as afterdepolarization. Entry of Ca2+ during depolarization triggers the opening of Ca2+-activated K+ channels and results in a persistent increase in K+ conductance called afterhyperpolarization (Additional Information 5.8).

Figure 5.12 Features of the Action Potential. Different ion channels contribute to the shape of the action potential in neurons. The resting membrane potential (RMP) (A) primarily depends on leak potassium (K+) channels. The ability to reach threshold is controlled by depolarizing slow sodium (Na+) currents and hyperpolarizing K+ currents through channels open at subthreshold potentials. At threshold (B), the sudden opening of fast inactivated Na+ channels triggers the action potential, followed by rapid inactivation of the channel (C). Repolarization primarily depends on the opening of delayed voltage-gated K+ channels. During repolarization, slow deinactivation of some Na+ channels elicits a depolarizing current (afterdepolarization) (D). This is followed by an afterhyperpolarization (E), which is primarily dependent on the opening of slow Ca2+-activated K+ channels.

Figure 5.12 Features of the Action Potential. Different ion channels contribute to the shape of the action potential in neurons. The resting membrane potential (RMP) (A) primarily depends on leak potassium (K+) channels. The ability to reach threshold is controlled by depolarizing slow sodium (Na+) currents and hyperpolarizing K+ currents through channels open at subthreshold potentials. At threshold (B), the sudden opening of fast inactivated Na+ channels triggers the action potential, followed by rapid inactivation of the channel (C). Repolarization primarily depends on the opening of delayed voltage-gated K+ channels. During repolarization, slow deinactivation of some Na+ channels elicits a depolarizing current (afterdepolarization) (D). This is followed by an afterhyperpolarization (E), which is primarily dependent on the opening of slow Ca2+-activated K+ channels.

Refractory Period

Membrane repolarization is critical to restoring neuronal excitability by reversing the inactivation of the voltage-gated Na+ channels. During increased Na+ conductance, the membrane cannot be stimulated to discharge again. A second stimulus at this time has no effect. Therefore, action potentials, unlike local potentials, cannot summate. This period of unresponsiveness is the absolute refractory period. As Na+ conductance returns to normal because of progressive inactivation of the voltage-gated channels, the membrane again becomes excitable; however, for a short period, it requires a larger stimulus to produce a smaller action potential. This is called the relative refractory period. After the relative refractory period, while the membrane is partially depolarized (afterdepolarization), it is closer to threshold and has an increased excitability; this is the supernormal period. During afterhyperpolarization, the membrane is hyperpolarized and stronger stimuli are required to elicit an action potential; this is the subnormal period.

Patterns of Firing of Action Potentials

The electrophysiologic properties of neurons vary according to the magnitude, cellular distribution, and pharmacologic sensitivity of ionic currents through voltage-gated Na+, Ca2+, and K+ channels. The heterogeneous repertoire and distribution of these channels results in a wide variety of patterns of neuronal activity in the brain. For example, some neurons, such as certain inhibitory GABAergic neurons in the cerebral cortex and Purkinje cells, are fast spiking and generate high-frequency action potentials. In contrast, projection neurons of the striatum are silent at rest but trigger a short duration burst of action potentials after reaching threshold. Bursting neurons generate regular bursts of action potentials separated by hyperpolarization of the membrane. Such neurons are important for rhythmic behavior such as breathing, walking, and chewing. Some neurons have slow spontaneous tonic activity that changes to transient burst firing in response to stimuli.

Frequency and Population Coding

Since the generation of an action potential is an all-or-none event, the amplitude of the action potential above threshold is the same regardless of the intensity of the stimulus. However, the more intense the stimulus, the shorter the time needed to reach threshold and the higher the frequency of discharge of action potentials. This strength-latency relationship allows information about the intensity of the stimulus to be encoded as a frequency (rate) code. Even at rest, many neurons exhibit intrinsic rhythmic fluctuations of the membrane potential. These fluctuations create subthreshold activation of the membrane, bringing it closer to threshold for the opening of voltage-gated Na+ channels. Thus, neurons have an active role in determining not only whether but also when a given input will trigger an action potential. Information can be conveyed by specific patterns of firing of individual neurons, including their firing frequency (rate code) or the intervals between individual action potentials (temporal code) or both. Information in the nervous system is encoded by the synchronized firing of networks or populations of neurons that may be widely distributed in the brain (population code). These networks are dynamic and include neurons interconnected by excitatory and inhibitory synapses (Chapter 11, “Consciousness System”).

Conduction of the Action Potential in Axons

Conduction of action potentials from the axon initial segment to the presynaptic terminal is critical for neuronal communication in the nervous system. The propagation of action potentials permits the nervous system to transmit information from 1 area to another. The velocity of propagation depends on the distribution of ion channels, the diameter of the axon, and the presence or absence of a myelin sheath.

Distribution of Ion Channels in Axons

In unmyelinated axons (eg, axons involved in the sensation of pain or temperature, axons of autonomic ganglion neurons, and many central axons), the voltage-gated Na+ and K+ channels responsible for the action potential are evenly distributed along the membrane of the axon. In contrast, myelinated axons consist of different compartments with unique distributions of ion channels. They include the axon initial segment, node of Ranvier, presynaptic axon terminal, paranode, juxtaparanode, and internodes covered by compact myelin (Figure 5.13). The axon initial segment has clusters of voltage-gated Na+ channels and is the site of initiation of the action potential. Like the axon initial segment, the nodes of Ranvier lack a myelin sheath and contain clusters of voltage-gated Na+ channels that mediate fast conduction of the action potential. A smaller number of voltage-gated K+ channels located in the nodes of Ranvier (and in the axon initial segment) control membrane excitability. In contrast, the paranode, and particularly the juxtaparanode, contain clusters of voltage-gated K+ channels that control both axonal excitability and firing frequency of action potentials. The presynaptic terminal contains voltage-gated Ca2+ channels clustered in so-called active zones that are critical for exocytosis of neurotransmitters from synaptic vesicles (see below). The selective distribution of ion channels in myelinated axons depends on their interactions with adaptor proteins that link the channels with the axonal cytoskeleton.

Figure 5.13 Distribution of Ion Channels in Myelinated Axons. Voltage-gated sodium (Na+) channels are clustered at the axon initial segment (the site of initiation of the action potential) and the nodes of Ranvier (involved in conduction of the action potential). The presence of voltage-gated potassium (K+) channels in these regions controls axonal excitability. The paranode, and particularly the juxtaparanode, contain clustered voltage-gated K+ channels that limit the probability of firing repetitive action potentials. The axon terminal contains clustered voltage-gated calcium (Ca2+) channels that are critical for exocytosis of neurotransmitters.

Figure 5.13 Distribution of Ion Channels in Myelinated Axons. Voltage-gated sodium (Na+) channels are clustered at the axon initial segment (the site of initiation of the action potential) and the nodes of Ranvier (involved in conduction of the action potential). The presence of voltage-gated potassium (K+) channels in these regions controls axonal excitability. The paranode, and particularly the juxtaparanode, contain clustered voltage-gated K+ channels that limit the probability of firing repetitive action potentials. The axon terminal contains clustered voltage-gated calcium (Ca2+) channels that are critical for exocytosis of neurotransmitters.

Cable Properties of the Membrane

The axon behaves like an electrical cable with properties of resistance and capacitance. Spread of electrical currents along axons depends on the passive electrical properties of the membrane, referred to as cable properties. When an area of axonal membrane is depolarized during an action potential, the flow of ionic currents produces an electrotonic potential (Figure 5.14). In the area of depolarization, Na+ ions carry positive charge inward. There is also a longitudinal flow of current both inside and outside the membrane. This flow of positive charge (current) toward nondepolarized regions internally and toward depolarized regions externally tends to depolarize the membrane in the areas that surround the region of the action potential. In normal tissue, this depolarization is sufficient to shift the membrane potential to threshold and thereby generate an action potential in the immediately adjacent membrane. Thus, the action potential spreads away from its site of initiation along an axon or muscle fiber. Because of the refractory period, the potential cannot reverse and spread back into an area just depolarized.

Figure 5.14 Current Flow and Voltage Changes in an Axon in the Region of an Action Potential. The voltage changes along the membrane are shown in the upper part of the diagram, and the spatial distribution of current flow is shown in the lower part as arrows through the axon membrane.

Figure 5.14 Current Flow and Voltage Changes in an Axon in the Region of an Action Potential. The voltage changes along the membrane are shown in the upper part of the diagram, and the spatial distribution of current flow is shown in the lower part as arrows through the axon membrane.

The velocity of conduction of the action potential along the membrane depends on the amount of longitudinal current flow in the form of electrotonic potentials and on the amount of current needed to produce depolarization in the adjacent membrane. Spread of electrotonic potentials along the axon is decremental and limited by 2 factors: 1) the high resistance of the axoplasm to longitudinal current flow and 2) the leakage of current through the axon membrane (axolemma) because of a relatively low membrane resistance and a relatively high membrane capacitance. Thus, the distance over which the local potential spreads depends on the ratio between the transverse membrane resistance and the longitudinal axoplasm resistance. This ratio is proportional to the radius of the axon. Therefore, conduction velocity is higher in large-diameter fibers than in small-diameter fibers, just as a larger electrical wire has a lower electrical resistance.

Importance of the Myelin Sheath

The most important determinant of the increase in conduction velocity in large-diameter axons is the presence of a myelin sheath, which serves as an electrical insulator. The myelin sheath is formed by Schwann cells in peripheral nerves and by oligodendrocytes in the central nervous system and consists of tightly packed membrane wrapped around the axon. This results in both an increase in membrane electrical resistance and a decrease in membrane capacitance that is proportional to the number of wrappings. These 2 changes prevent the transverse dissipation of current across the membrane; thus, myelin effectively insulates the axon.

In a myelinated axon, the membrane is bare only at the nodes of Ranvier; consequently, transmembrane current flow occurs almost exclusively at the nodal area. The presence of the myelin sheath promotes the clustering of voltage-gated Na+ channels at the nodes. When current flow opens enough Na+ channels to reach threshold in the nodal area, it results in many more Na+ channels opening, an influx of Na+ ions, and, thus, generation of an action potential. The action potential at 1 node of Ranvier produces sufficient longitudinal current flow to depolarize adjacent nodes to threshold, thereby propagating the action potential along the nerve in a skipping manner called saltatory conduction (Figure 5.15).

Figure 5.15 Saltatory Conduction Along an Axon From Left to Right. The charge distribution along the axon is shown with an action potential (depolarization) at the second node of Ranvier (N2). Current flow spreads to the third node of Ranvier (N3). I1, I2, and I3 indicate internodes; N1, first node of Ranvier.

Figure 5.15 Saltatory Conduction Along an Axon From Left to Right. The charge distribution along the axon is shown with an action potential (depolarization) at the second node of Ranvier (N2). Current flow spreads to the third node of Ranvier (N3). I1, I2, and I3 indicate internodes; N1, first node of Ranvier.

Synaptic Transmission

A synapse is a specialized contact zone where 1 neuron communicates with another neuron. There are 2 types of synapses: chemical and electrical. The contact zone between an axon terminal and a muscle fiber or other nonneural target is a neuroeffector junction.

General Features of Chemical Synapses

Chemical synapses are the more common form of communication in the nervous system. They are fully discussed in Chapter 6 (“Neurochemistry”), so only a few salient features are emphasized here. A chemical synapse consists of a presynaptic component (containing synaptic vesicles), a postsynaptic component (dendrite, soma, or axon), and an intervening space called the synaptic cleft (Figure 5.16). In the central nervous system, processes from the astrocytes form a sheath around the presynaptic and postsynaptic elements of the chemical synapse and actively participate in regulation of synaptic transmission, creating a tripartite synapse. Chemical synapses involve 2 fundamental processes: 1) release of neurotransmitter by synaptic vesicle exocytosis upon arrival of the action potential at the presynaptic axon terminal and 2) binding of the neurotransmitter to its postsynaptic receptors, triggering a postsynaptic potential.

Figure 5.16 Synaptic Transmission. A, In a resting synapse, both the presynaptic axon terminal and the postsynaptic membrane are normally polarized. B, In an active synapse, an action potential invades the axon terminal (from the left in the diagram) and depolarizes it. Depolarization of the axon terminal of a presynaptic neuron results in the release of neurotransmitter from the terminal. The neurotransmitter diffuses across the synaptic cleft and produces local current flow and a synaptic potential in the postsynaptic membrane, which initiates the effector activity (neuronal transmission, neurotransmitter release, muscle contraction, or hormonal secretion). Ca2+ indicates calcium.

Figure 5.16 Synaptic Transmission. A, In a resting synapse, both the presynaptic axon terminal and the postsynaptic membrane are normally polarized. B, In an active synapse, an action potential invades the axon terminal (from the left in the diagram) and depolarizes it. Depolarization of the axon terminal of a presynaptic neuron results in the release of neurotransmitter from the terminal. The neurotransmitter diffuses across the synaptic cleft and produces local current flow and a synaptic potential in the postsynaptic membrane, which initiates the effector activity (neuronal transmission, neurotransmitter release, muscle contraction, or hormonal secretion). Ca2+ indicates calcium.

Chemical synapses have 4 unique main features: 1) The brief time required for chemical events to occur results in a synaptic delay between the arrival of the action potential to the axon terminal and the initiation of the postsynaptic event. 2) The transmission of information is anterograde, from the presynaptic to the postsynaptic neuron. 3) Because nerve impulses from many sources impinge on single cells in the central and peripheral nervous systems, synaptic potentials summate both temporally and spatially. 4) Each synaptic input may be mediated by different neurotransmitters with different effects on the neuron. Thus, a single neuron can integrate activity from many sources. When the membrane potential reaches threshold, an action potential is generated.

Presynaptic Events

Chemical synapses are mediated by a wide variety of neurotransmitters released from presynaptic vesicles. These include amino acids (glutamate, γ‎-aminobutyric acid [GABA], and glycine); acetylcholine; monoamines (dopamine, norepinephrine, serotonin, and histamine); neuropeptides (endogenous opioids); purines (including ATP); and lipoid mediators (endocannabinoids). The presynaptic events in chemical neurotransmission include 1) synthesis of the chemical transmitter, 2) incorporation into synaptic vesicles, 3) mobilization of vesicles and their docking at the presynaptic active zones containing clustered voltage-gated Ca2+ channels, 4) Ca2+-triggered exocytosis and neurotransmitter release, 5) vesicle recycling (primarily by endocytosis), and 6) presynaptic reuptake of the neurotransmitter (Chapter 6, “Neurochemistry”).

Amino acid neurotransmitters and acetylcholine are synthesized from intermediates of the Krebs cycle; monoamines are synthesized from essential amino acid precursors by the action of specific enzymes. All these neurotransmitters are incorporated into synaptic vesicles at the level of the presynaptic terminal by different types of proton-coupled vesicular transporters. In contrast, neuropeptides are synthesized in the cell body and transported in secretory vesicles along the axon to the synaptic terminal. The synaptic vesicles are mobilized from their sites of attachment at the cytoskeleton and dock close to the active zones through complex interactions mediated by various proteins located in both the synaptic vesicle and the presynaptic membrane.

Neurotransmitter release is triggered by the influx of Ca2+ through voltage-gated channels that open in response to the arrival of an action potential in the presynaptic terminal (Figure 5.16). The vesicles are then recycled and the neurotransmitter is cleared from the synaptic cleft by Na+-coupled membrane transporters located in the presynaptic terminal and astrocytes. Neurotransmitters then undergo further metabolism in the mitochondria. The only exceptions are acetylcholine and neuropeptides, which do not undergo reuptake but are hydrolyzed at the synaptic cleft (Chapter 6, “Neurochemistry”).

Postsynaptic Events

Neurotransmitters act through 2 main classes of receptors: ligand-gated receptors and G (guanyl-nucleotide-binding) protein–coupled receptors. Ion channels that open in response to the chemical transmitter, allowing the rapid influx of cations (Na+ and Ca2+) or Cl, are called ligand-gated receptors. These 2 types of receptors mediate 2 different types of synaptic interactions, referred to as classical neurotransmission and neuromodulation (Table 5.5).

Table 5.5 Differences Between Classical Neurotransmission and Neuromodulation

Characteristic

Classical Neurotransmission

Neuromodulation

Receptor type

Neurotransmitter (ligand)-gated ion channels (ionotropic receptors)

G protein–coupled receptors (metabotropic receptors)

Neurotransmitters

Glutamate, GABA, glycine, and acetylcholine (in some cases, also serotonin and ATP)

Glutamate, GABA, acetylcholine, monoamines, neuropeptides, and lipid mediators

Effect

  • Opening of ligand-gated Na+ or Ca2+ channels (fast EPSP)

  • Opening of ligand-gated Cl channels (fast IPSP)

  • Opening of voltage-gated K+ channels

  • Closure of voltage-gated K+ channels

  • Opening of postsynaptic voltage-gated Ca2+ channels

  • Closure of presynaptic voltage-gated Ca2+ channels

Function

Fast, precise, point-to-point synaptic excitation or inhibition

  • Control of neuronal excitability

  • Control of neurotransmitter release

Abbreviations: ATP, adenosine triphosphate; Ca2+, calcium; Cl, chloride; EPSP, excitatory postsynaptic potential; GABA, γ‎-aminobutyric acid; IPSP, inhibitory postsynaptic potential; K+, potassium; Na+, sodium.

Classical Neurotransmission

The binding of neurotransmitters to neurotransmitter (ligand)-gated ion channels elicits fast ion influx in the postsynaptic target, eliciting fast postsynaptic potentials. These ligand-gated channels are clustered at the postsynaptic membrane just across from the presynaptic active zones, which allows for fast and localized synaptic action. Influx of cations elicits rapid depolarization of the membrane, called fast excitatory postsynaptic potentials (EPSPs) because they allow the membrane to reach threshold to trigger the action potential. Important examples of excitatory neurotransmitters that activate cation channels are glutamate, acting through different ionotropic receptors, and acetylcholine, acting through nicotinic receptors.

In contrast, the influx of Cl rapidly brings the membrane potential toward the equilibrium potential of this ion (–75 mV). This results in a fast inhibitory postsynaptic potential (IPSP) that prevents the membrane from reaching the threshold for action potentials. The inhibitory neurotransmitters that activate Cl channels include GABA and glycine. Fast excitatory or inhibitory potentials allow rapid, point-to-point transfer of excitatory or inhibitory information between cells.

Neuromodulation

The second class of neurotransmitter receptors, G protein–coupled receptors, mediates the effects of monoamines and neuropeptides and some of the effects of acetylcholine, glutamate, and GABA. Many types of G protein–coupled receptors, unlike ligand-gated receptors, indirectly affect the function of ion channels. The activation of G protein–coupled receptors increases or decreases the permeability of voltage-gated ion channels either through interactions of G protein subunits with the ion channel or through phosphorylation of the channel triggered by molecules generated in response to activation of the G protein–coupled receptor. The main targets of regulation by G protein–coupled receptors are several types of K+ channels and voltage-gated Ca2+ channels. The permeability of these channels may be increased or decreased in response to different G proteins.

Through these mechanisms, activation of the G protein–coupled receptors does not elicit a fast excitatory or inhibitory postsynaptic response but rather a change in neuronal excitability. Potassium channels are the main target for neuromodulatory signals. Signals that lead to closure of K+ channels (thus moving the membrane potential away from the equilibrium potential of this ion) elicit slow membrane depolarization toward threshold, which increases excitability and the probability of triggering an action potential. In contrast, G protein–coupled mechanisms that lead to the opening of K+ channels (thus moving the membrane potential toward the equilibrium potential) elicit slow membrane hyperpolarization (away from threshold), which decreases neuronal excitability and responsiveness to other stimuli.

Complexity of Synaptic Effects

Multiple Effects of Neurotransmitters

Many features provide for the complexity of chemical neurotransmission: 1) A single presynaptic terminal may release more than 1 neurotransmitter. 2) A single neurotransmitter may exert multiple synaptic effects (fast excitation or inhibition, and facilitatory or inhibitory neuromodulation) through different subtypes of receptors. 3) Crosstalk between neurotransmitters allows interaction at the level of common postsynaptic signaling mechanisms or presynaptically inhibits the release of each other.

Presynaptic Effects of Neurotransmitters

A neurotransmitter may also act through ion channel receptors or G protein–coupled receptors located in the presynaptic membrane. Through these presynaptic receptors, neurotransmitters may regulate their own release or the release of other neurotransmitters. Neurotransmitters may inhibit neurotransmitter release from the presynaptic axon terminal; this is called presynaptic inhibition. Most such presynaptic receptors are G protein–coupled receptors that trigger the closure of voltage-gated Ca2+ channels, thus inhibiting exocytosis. As a feedback mechanism, many neurotransmitters inhibit their own release by acting on presynaptic inhibitory autoreceptors. Presynaptic inhibition may occur through axoaxonic synapses. The inhibitory axon elicits a partial depolarization that decreases the magnitude of the action potential in the presynaptic axon, thus reducing the number of voltage-gated channels that open and the number of synaptic vesicles that release neurotransmitters.

Interactions Among Excitatory and Inhibitory Synapses

There are several patterns of synaptic interactions (Figure 5.17). One pattern of synaptic microcircuitry is that of synaptic divergence, by which a single excitatory or inhibitory axon terminal synapses with multiple dendrites. If the synapse is excitatory, this pattern amplifies the activity of a single axon into simultaneous excitation in many postsynaptic neurons. Another example of divergence occurs in many relay nuclei of the sensory and motor systems. In these nuclei, the basic synaptic circuit is a triad consisting of 1) an excitatory afferent axon, 2) the cell body and dendrites of an excitatory projection neuron, and 3) a local inhibitory interneuron that synapses with the projection neuron. This pattern of connectivity provides a mechanism for feedforward inhibition. Collaterals from the axon of the projection neuron also activate an inhibitory interneuron that provides feedback inhibition of the corresponding excitatory projection neuron. In some areas of the central nervous system, such as the dorsal horn of the spinal cord, inhibitory neurons make axoaxonic synapses with primary excitatory afferents, reducing the probability of excitatory neurotransmitter release; this is presynaptic inhibition.

Figure 5.17 Interactions Among Excitatory and Inhibitory Synapses. Synaptic divergence (A) occurs when a single excitatory or inhibitory axon terminal synapses with multiple dendrites. There may also be the convergence of excitatory and inhibitory inputs (B) on a single dendrite or soma. A synaptic triad (C) consists of an excitatory afferent axon, the cell body and dendrites of an excitatory projection neuron, and a local inhibitory interneuron that synapses with the projection neuron. This provides a mechanism for feedforward inhibition (D). Collaterals from the axon of the projection neuron also activate an inhibitory interneuron that provides feedback inhibition (E). Inhibitory neurons can make axoaxonic synapses with primary excitatory afferents, producing presynaptic inhibition (F).

Figure 5.17 Interactions Among Excitatory and Inhibitory Synapses. Synaptic divergence (A) occurs when a single excitatory or inhibitory axon terminal synapses with multiple dendrites. There may also be the convergence of excitatory and inhibitory inputs (B) on a single dendrite or soma. A synaptic triad (C) consists of an excitatory afferent axon, the cell body and dendrites of an excitatory projection neuron, and a local inhibitory interneuron that synapses with the projection neuron. This provides a mechanism for feedforward inhibition (D). Collaterals from the axon of the projection neuron also activate an inhibitory interneuron that provides feedback inhibition (E). Inhibitory neurons can make axoaxonic synapses with primary excitatory afferents, producing presynaptic inhibition (F).

Another pattern of synaptic interaction is the convergence of inputs on a single neuron. When several stimuli are excitatory, the resulting excitatory postsynaptic potentials may undergo temporal or spatial summation. Synaptic convergence also provides the basis for algebraic summation of excitatory and inhibitory postsynaptic potentials. One important aspect of inhibitory neurotransmission is the localization of the inhibitory (typically GABAergic) synapse. An inhibitory synapse targeting the axon initial segment (the site of generation of the action potential) has a powerful effect on the output of the neuron, determining the probability of initiating an action potential. In contrast, an inhibitory synapse located at the dendritic branches or dendritic spines affects the amplitude of only the local potentials at that level.

Dendritic Integration of Synaptic Signals

Dendrites, the main receiving elements of neurons, receive and integrate information from tens or even hundreds of thousands of presynaptic inputs. In many neurons of the central nervous system, including pyramidal cells of the cerebral cortex, excitatory synaptic inputs target the dendritic spines, whereas inhibitory inputs target the dendritic shafts. Since the action potential is initiated at the axon initial segment, the ability of synaptic inputs to trigger depolarization depends on their ability to reach the cell body. This depends on 1) the passive properties of the dendritic membrane (resistance and capacitance) and its geometry and 2) the presence of dendritic voltage-gated Na+ and Ca2+ channels that produce dendritic spikes to boost the EPSPs and allow them to depolarize the axon initial segment.

Astrocyte Signaling in the Central Nervous System

Synaptic activity affects the function of astrocytes, which are integral components of the synaptic unit. For example, synaptic release of the excitatory neurotransmitter glutamate provides a signal to the astrocytes around the synapse, resulting in increased intracellular Ca2+ and increased energy metabolism in astrocytes. Glutamate exerts these effects on astrocytes through receptors in astrocytes and through increased ATP consumption as a result of its uptake after release from an excitatory synapse. In response to these synaptic signals, astrocytes release several molecules (including glutamate and ATP, which regulate synaptic transmission) and lactate (which provides a fuel for energy metabolism).

Electrical Synapses

Although most synapses in the nervous system use chemical neurotransmitters, neurons may also interact through gap junctions adjoining the membrane of 2 adjacent neurons. Each membrane contributes a hemichannel, composed of a protein called connexin, which forms a gap junction channel that allows bidirectional flow of ion current. Transmission across the electrical synapse is rapid, without the synaptic delay of chemical synapses. Also, electrical synapses are bidirectional, in contrast to chemical synapses, which transmit signals primarily in only 1 direction. Gap junctions occur between different subtypes of neurons and are also typical of astrocytes. Astrocytes connected by gap junctions form a functional syncytium that provides a pathway for the transmission of electrical and chemical information over large distances in the central nervous system.

Clinical Correlations: Transient Neurologic Disorders

Definition and Pathophysiologic Mechanisms

The mechanisms responsible for neuronal excitability, impulse conduction, and synaptic transmission in the central and peripheral nervous systems may be altered transiently to produce either loss of activity or overactivity of neurons due to changes in their excitability (Figure 5.18). Loss of activity results in negative symptoms (functional deficit) such as weakness or sensory loss, whereas increased activity results in positive symptoms such as abnormal movements or spontaneous sensation. Both types of transient alterations are of relatively short duration (seconds to hours) and reversible. Transient disorders may be focal or generalized and may affect the central or peripheral nervous systems (or both) (Table 5.6).

Figure 5.18 Main Pathophysiologic Mechanisms and Causes of Transient Neurologic Disorders.

Figure 5.18 Main Pathophysiologic Mechanisms and Causes of Transient Neurologic Disorders.

Table 5.6 Examples of Transient Disorders

Excitability

Focal Disorders

Generalized Disorders

Central

Peripheral

Central

Peripheral

Increased

  • Focal seizure

  • Tonic spasm

  • Paroxysmal pain

  • Paresthesia

  • Muscle cramp

  • Generalized seizure

  • Stiff person syndrome

  • Myotonia

  • Tetany

Decreased

  • Transient ischemic attack

  • Migraine aura

Nerve compression palsy

  • Syncope

  • Hypoglycemia

  • Cataplexy

  • Periodic paralysis

  • Myasthenia gravis and myasthenic syndromes

Transient disorders reflect disturbances in neuronal excitability due to membrane abnormalities and may be due to many mechanisms (Figure 5.18). The most common mechanisms are transient dysfunction of ATP-driven pumps due to energy failure and abnormalities in ion permeability from genetic, immune, or toxic causes (Table 5.7).

Table 5.7 Common Mechanisms and Causes of Transient Disorders

Cause

Mechanism

Examples

Energy failure

  • Impaired activity of Na+,K+-ATPase and other ATP-driven pumps

  • Impaired astrocytic uptake of glutamate

  • Inability to maintain resting membrane potential, leading to depolarization block and excitotoxicity

  • Hypoxia

  • Ischemia

  • Hypoglycemia

  • Status epilepticus

Channelopathies

Loss of function of voltage- or neurotransmitter-gated channels, leading to depolarization block or abnormal synaptic transmission

  • Genetic disorders

  • Autoimmune disorders

  • Toxins

  • Pharmacologic blockade

Spreading depression

Spreading depolarization block in the cerebral cortex due to inability of astrocytes to buffer extracellular K+ and uptake glutamate

Migraine aura

Electrolyte disorders

Increased or decreased excitability due to abnormalities in resting membrane potential or threshold for opening voltage-gated Na+ channels

  • Hypokalemia

  • Hyperkalemia

  • Hypocalcemia

Demyelination

Increased membrane capacitance and inability to reach threhold to depolarize the nodes of Ranvier, leading to conduction slowing or blockade

  • Multiple sclerosis

  • Demyelinating polyradiculoneuropathy

Abbreviations: ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; K+, potassium; Na+, sodium.

Energy Failure

Energy metabolism is necessary for maintenance of the membrane potential by the ATP-coupled Na+-K+ pump. Most of the ATP produced in the nervous system by aerobic metabolism of glucose is used to maintain the activity of this pump. Conditions such as hypoxia, ischemia, hypoglycemia, and seizures affect the balance between energy production and energy consumption of neurons and cause energy failure and thus impaired activity of Na+,K+-ATPase (Figure 5.19). If the active transport process stops, the cell accumulates Na+ and loses K+ and the membrane potential progressively decreases. This depolarization has 2 consequences. First, a transient increase in neuronal excitability may occur as the membrane potential moves closer to threshold for opening voltage-gated Na+ channels and triggering action potentials. This may produce a paroxysmal discharge of the neuron or axon. Second, if depolarization persists, Na+ channels remain inactivated and the neuron becomes inexcitable. This depolarization blockade causes a focal deficit, such as focal paralysis or anesthesia, or a generalized deficit, such as paralysis or loss of consciousness (Figure 5.19; Additional Information 5.9).

Figure 5.19 Effects of Increasing Severity of Energy Failure. With progressive failure of adenosine triphosphate (ATP)-driven pumps, potassium (K+) accumulates extracellularly, and sodium (Na+) and calcium (Ca2+) accumulate intracellularly. This produces progressive neuronal depolarization. With partial depolarization, the resting potential moves closer to the threshold for triggering an action potential; this results in a transient increase in neuronal excitability, which may be manifested by paresthesias or seizures. With further depolarization, the membrane potential is at a level that maintains inactivation of Na+ channels, preventing further generation of action potentials and, thus, reducing neuronal excitability. This constitutes depolarization block, which results in transient and reversible deficits such as paralysis or loss of consciousness. If the energy failure is severe and prolonged, the excessive accumulation of intracellular Ca2+ triggers various enzymatic cascades that lead eventually to neuronal death and irreversible loss of function.

Figure 5.19 Effects of Increasing Severity of Energy Failure. With progressive failure of adenosine triphosphate (ATP)-driven pumps, potassium (K+) accumulates extracellularly, and sodium (Na+) and calcium (Ca2+) accumulate intracellularly. This produces progressive neuronal depolarization. With partial depolarization, the resting potential moves closer to the threshold for triggering an action potential; this results in a transient increase in neuronal excitability, which may be manifested by paresthesias or seizures. With further depolarization, the membrane potential is at a level that maintains inactivation of Na+ channels, preventing further generation of action potentials and, thus, reducing neuronal excitability. This constitutes depolarization block, which results in transient and reversible deficits such as paralysis or loss of consciousness. If the energy failure is severe and prolonged, the excessive accumulation of intracellular Ca2+ triggers various enzymatic cascades that lead eventually to neuronal death and irreversible loss of function.

Channelopathies

Genetic or autoimmune disorders may affect the function of ion channels directly or by affecting auxiliary proteins (Table 5.8).

Table 5.8 Examples of Genetic and Autoimmune Channelopathies

Channel

Clinical Manifestation

Genetic

Neuronal voltage-gated Na+ channels (in inhibitory interneurons)

Epilepsy

Neuronal voltage-gated K+ channels

Epilepsy

Episodic ataxia

Neuronal voltage-gated Ca2+ channels

Epilepsy

Migraine

Ataxia

Neuronal GABA receptor

Epilepsy

Muscle nicotinic receptor

Congenital myasthenic syndrome

Muscle voltage-gated Na+ channel

Periodic paralysis

Autoimmune

Neuronal voltage-gated K+ channel complex

Limbic encephalitis with amnesia and seizures

Glutamate-activated cation channels

Encephalitis with behavioral and cognitive manifestations and seizures

GABA receptors

Seizures

Axonal voltage-gated K+ channel complex

Neuromuscular hyperexcitability

Presynaptic voltage-gated Ca2+ channels (P/Q type) at the neuromuscular junction

Lambert-Eaton myasthenic syndrome

Muscle nicotinic acetylcholine receptor

Myasthenia gravis

Ganglionic nicotinic acetylcholine receptor

Autoimmune autonomic ganglionopathy

Abbreviations: Ca2+, calcium; GABA, γ‎-aminobutyric acid; K+, potassium; Na+, sodium.

Genetic Disorders

Mutations that alter the amino acid composition of ion channel subunits produce either pathologic loss of function (impaired activation) or pathologic gain of function (impaired inactivation leading to persistent depolarization and secondary inexcitability due to depolarization blockade). Genetic channelopathies may affect voltage- or neurotransmitter-gated Na+, K+, or Ca2+ channels in the central or peripheral nervous system. For example, mutations leading to loss of function of voltage-gated Na+ channels in inhibitory GABAergic interneurons lead to generalized epilepsy due to excessive excitability of cortical pyramidal cells. Epilepsy may also be due to mutations of different types of K+ or Ca2+ channels. Genetic channelopathies may also produce episodic cerebellar ataxia. Muscle channelopathies affecting the voltage-gated Na+, Ca2+, K+, or Cl channels may manifest with episodic weakness (called periodic paralysis) or increased muscle excitability producing impaired muscle relaxation (called myotonia) or both.

Immune Disorders

Autoantibodies may affect ion channel function directly or by affecting their interaction with critical associated proteins that are part of the functional channel complex. For example, antibodies against the voltage-gated K+ channel complex may produce limbic encephalitis, characterized by personality and memory abnormalities and seizures. Similar manifestations occur in disorders associated with antibodies against subunits of glutamate or GABA receptors.

Autoantibodies may also block ion channels involved in neuromuscular transmission and produce reversible muscle fatigue or paralysis. The typical example is myasthenia gravis due to antibodies against muscle nicotinic acetylcholine receptors in muscle membranes at motor end plates. Antibodies against voltage-gated Ca2+ channels (P/Q channels) interfere with the release of acetylcholine from motor nerve endings, as in Lambert-Eaton myasthenic syndrome. In many cases, autoimmune channelopathies may be a paraneoplastic manifestation of an underlying nonneurologic neoplasm, such as small cell lung carcinoma, breast adenocarcinoma, or thymoma. This is because many types of neoplastic cells share membrane antigens with neurons and muscle cells.

Electrolyte Disorders

Disorders affecting serum electrolyte levels may produce transient changes in the excitability of nerve and muscle. The effect of this change depends on the state of membrane permeability. An alteration in extracellular K+ mainly affects the resting membrane potential. Changes in the serum concentration of K+ mainly affect excitability in the periphery (peripheral axons and skeletal or cardiac muscle). A decrease in extracellular K+, as when this ion is lost because of disease (vomiting or diarrhea) or medication (diuretics), increases the transmembrane K+ gradient and thereby the negativity of the equilibrium potential of K+. This results in membrane hyperpolarization, which makes the cell less excitable and may produce severe weakness or cardiac arrhythmias (or both). In contrast, an increase in extracellular K+, as in renal or adrenal failure, decreases the concentration gradient and thus the equilibrium potential of K+, reducing the negativity of the resting potential and leading to membrane depolarization. Small or brief increases in extracellular K+ may increase the probability of reaching the threshold for opening Na+ channels and generating action potentials, transiently increasing cell excitability and spontaneous firing of action potentials. A large increase in extracellular K+, in contrast, produces persistent depolarization and thus inactivation of voltage-gated Na+ channels, rendering the membrane inexcitable (depolarization block).

Calcium acts primarily as a membrane stabilizer by increasing the voltage required to open ion channels. Thus, hypocalcemia increases excitability and may produce spontaneous activity, resulting in excess muscle contraction (tetany), spontaneous sensory symptoms (paresthesias), and, if severe, seizures. Hypercalcemia does not produce demonstrable changes, except at very high concentrations of Ca2+.

Interactions of Mechanisms Affecting Neuronal Excitability

Epilepsy and migraine aura result from pathophysiologic responses to energy failure (which impairs ATPase pumps), ion channel dysfunction, and abnormal electrolyte homeostasis.

Seizures

Seizures are transient episodes of supratentorial origin in which there is abrupt and temporary alteration of cerebral function (Chapter 11, “Consciousness System”). They are produced by spontaneous, excessive discharge of cortical neurons caused by several pathophysiologic mechanisms. Excessive excitation or abnormal rhythmic synchronized activity may occur in focal areas of the cerebral cortex (focal seizures) or over the entire cerebral cortex (generalized seizures). A focal or generalized increase in neuronal excitability may result from energy failure producing transient depolarization or lack of local inhibition. Thus, several pathophysiologic mechanisms may lead to seizures. These include 1) genetic or acquired channelopathies that affect excitability of cortical neurons; 2) imbalance between excitatory and inhibitory synaptic influences (ie, increased glutamatergic or reduced GABAergic neurotransmission) promoting synchronized activity of neuronal populations; and 3) astrocyte dysfunction, with an inability to clear synaptic glutamate and buffer excessive extracellular K+ after excitatory synaptic activity.

Cortical Spreading Depression

Cortical spreading depression is the mechanism underlying focal neurologic deficits during attacks of migraine. These deficits typically precede the onset of the headache and are known as a migraine aura. Cortical spreading depression may also contribute to progression of neurologic deficits during focal brain ischemia. It consists of a short-lasting depolarization wave that moves across the cortex at a rate of 3 to 5 mm/min and produces a brief phase of excitation, followed by prolonged neuronal depression due to depolarization block. During spreading depression, there is an abrupt increase in the brain of extracellular K+ and a release of glutamate, reflecting primarily dysfunction of astrocytes. The spread of the depolarization may occur partly through the gap junctions of astrocytes.

Pharmacologic and Toxic Channel Blockade

Voltage- and neurotransmitter-gated ion channels are the targets of drugs used for management of several neurologic disorders (Table 5.9). For example, blockade of Na+ channels in sensory axons by local anesthetic agents produces anesthesia. Ion channels are important targets of drugs used to treat disorders associated with excessive neuronal excitability such as epilepsy.

Table 5.9 Examples of Therapeutic Drugs Acting on Ion Channels

Channel

Drug

Therapeutic Use

Voltage-gated Na+ channels (blockers)

  • Lidocaine

  • Carbamazepine or phenytoin

  • Mexiletine

  • Local anesthesia

  • Seizures

  • Neuropathic pain

  • Cardiac arrhythmia

Voltage-gated Ca2+ channels (blockers)

  • Verapamil

  • Nifedipine or nimodipine

  • Cluster headache

  • Cardiac arrhythmia

  • Hypertension

Voltage-gated K+ channels (blockers)

3,4-Diaminopyridine

Lambert-Eaton myasthenic syndrome

GABAA receptor-gated Cl channels (allosteric modulators)

Benzodiazepines

  • Seizures

  • Spasticity

  • Insomnia

  • Anxiety

Abbreviations: Ca2+, calcium; Cl, chloride; GABAA, γ‎-aminobutyric acid A; K+, potassium; Na+, sodium.

Effects of Toxins

Several biologic toxins exert their actions by altering ion channels or synaptic transmission or both. For example, tetrodotoxin produced by certain fish and saxitoxin found in shellfish block voltage-gated Na+ channels and cause paralysis. A fundamental difference between therapeutic drugs and toxins affecting the channels is that therapeutic drugs, such as phenytoin, bind to the inner portion of the channel pore and therefore typically block channels that abnormally remain in the open state for long periods. In contrast, biologic toxins generally bind to the extracellular portion of the channels and therefore prevent opening of the channels in response to physiologic stimuli. Clostridial toxins, such as tetanus and botulinum toxins, prevent the release of neurotransmitter by destroying proteins essential for the docking of synaptic vesicles at the active zone.

Consequences of Demyelination

Demyelination is an important mechanism of neurologic disease. Myelin disorders may be caused by genetic defects in myelin composition or, more commonly, by acquired disorders of myelin. Acquired disorders of myelin are frequently due to immune-mediated mechanisms. In the peripheral nervous system, these disorders include acute and chronic inflammatory demyelinating neuropathies. In the central nervous system, the most important example is multiple sclerosis. In demyelinating diseases, not only is myelin lost but also Na+ and K+ channels are redistributed. The loss of myelin means that the insulation of the axon is lost and the electrical current is dissipated because of increased capacitance and decreased resistance of the membrane. The loss of myelin around the internodes and the loss of the concentration of Na+ channels at the nodes of Ranvier interfere with saltatory conduction and slow nerve conduction or, in severe cases, cause conduction block. Conduction block produces deficits such as paralysis and loss of sensation. Transient conduction block may be caused by drugs (eg, local anesthetics) that block Na+ channels or by nerve compression.

Additional Resources

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