Points of Interest
• A number of abnormal behaviors found in autism can be produced in rodent models. None of these behaviors are specific for autism, however.
• Human disorders caused by single-gene mutations that exhibit features of autism provide proof-of-principle for the role of genetics in autism. Similarly, studies showing that maternal thalidomide, valproate, or infection can increase the risk for features of autism in the offspring provide proof-of-principle for the role of environmental factors. Both the environmental and genetic factors can be very effectively modelled in mice.
• Certain neuropathologies that are relatively common in autism can be reproduced in rodent models.
Animal models of many neurological diseases (Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis) have proven enormously useful for determining the roles of genes and environment, for understanding pathogenesis, and for testing potential therapeutic approaches. There is some skepticism, however, concerning models of psychiatric or mental illnesses (e.g., autism, schizophrenia, depression). After all, can cognitive abnormalities or language deficits be detected in animals? However, to give up on this approach would deny the application of powerful genetic and molecular tools to these critical illnesses. Moreover, animal models need not be perfect mimics of human diseases to be valuable. This is clear from the extensive and productive use of genetic mouse models for Huntington’s and other neurodegenerative diseases, which do not exhibit the severe loss of particular types of neurons that characterize these disorders. The power of animal models is in the examination of key features of a disease, and the relevance of an animal model should be judged by how well it reflects one or more features of that disease, which may include genetics, neuropathology, behavior, etiology, electrophysiology, or molecular changes.
Autism is a particularly difficult case for animal studies because it has a heterogeneous behavioral phenotype, the susceptibility genes have not been firmly identified, and it does not have a pathognomonic histology that allows definitive diagnosis. Nonetheless, autism does have generally agreed upon features that are distinctive, such as a deficit of Purkinje cells (PCs), decreased hippocampal γ-aminobutyric acid (GABAA) receptors, and elevated levels of brain-derived neurotrophic factor (BDNF) and platelet serotonin (5-HT) (Palmen et al., 2004; Pardo & Eberhart, 2007; Amaral et al., 2008). There is also striking evidence for immune dysregulation in the autistic brain and cerebrospinal fluid (Pardo et al., 2006; Arion et al., 2007; Chez et al., 2007; Pardo & Eberhart, 2007; Morgan et al., 2010). Moreover, some of the characteristic behavioral features of autism can be assayed in animals, such as neophobia, abnormal social interactions, stereotyped and repetitive motor behaviors, communication deficits (ultrasonic vocalizations; USVs), enhanced anxiety, abnormal pain sensitivity, disturbed sleep patterns, abnormal eye blink conditioning, and deficits in sensorimotor gating (prepulse inhibition; PPI) (Silverman et al., 2010).
Although autism has a strong genetic basis, it is not a monogenic disorder, and thus it is not possible to establish an immediately relevant genetic mouse model, as was done with Huntington’s disease. Nonetheless, there are several genetic changes that do entail an elevated risk for autism, and mouse models of these changes share some features with the human disorder. There are also several human disorders caused by single gene mutations that display autistic features and mouse mutants of these mutations display behavior or neuropathology relevant to autism. In addition, models based on autism etiology are valuable, and there are several known environmental risk factors that are being successfully modeled in rodents. Finally, there are brain lesion models of interest. Therefore, even at this early stage of analysis, it is clear that various models can be used to study how particular genes influence certain autism endophenotypes, and how known environmental risk factors influence such endophenotypes. It will also be interesting to determine how a particular genotype influences the response to an environmental risk factor, and vice versa. There are currently very few examples of such gene-environment interactions in mouse models. This chapter discusses current genetic, environmental risk factor and lesion models. Several other authors have reviewed various aspects of animal models related to autism (Murcia et al., 2005; Tordjman et al., 2007; Moy & Nadler, 2008).
Thalidomide and Valproic Acid
Prenatal or early postnatal drug exposure can increase autism risk. Comorbidity of Moebius syndrome and autism support a correlation between autism and the use of the prostaglandin misoprostol, a drug historically administered for labor induction or abortion (Miller et al., 2004). Case studies of fetal alcohol syndrome also suggest that prenatal exposure to ethanol increases risk for autism (Nanson, 1992). Perhaps most clearly associated with autism, however, are the teratogens thalidomide (Stromland et al., 1994) and valproic acid (VPA; valproate) (Christianson et al., 1994). Not only can these drugs cause an array of birth defects, they also increase the incidence of autism when administered early in human pregnancy (Miyazaki et al., 2005).
The use of thalidomide led to the discovery of a window of vulnerability for the development of autism (Figure 52-1). During the 1950s and 60s, thalidomide treatment of morning sickness resulted in thousands of offspring with severe malformations. Since the timing of drug exposure leads to specific types of craniofacial defects, the defects seen in the autistic offspring could be used to determine when these offspring were exposed. In this way, vulnerability to autism was pinpointed to days 20 to 24 of gestation, the time of neural tube closure and formation of motor nuclei and cranial nerves. Importantly, there is some evidence that idiopathic autism cases may also exhibit abnormalities in the cranial nerve nuclei and other neuropathologies that originate during fetal brain development (Schneider & Przewlocki, 2005; Palmen et al., 2004).
A few laboratories have translated maternal thalidomide exposure into rodent models. Exposure of rats to thalidomide on embryonic day 9 (E9) yields adult offspring with hyperserotonemia in the plasma (as in autism), hippocampus, and frontal cortex (Narita et al., 2002), with altered distribution of serotonergic neurons in the raphe nuclei (Miyazaki et al., 2005). These offspring also display hyperactivity in the open field and decreased learning in the radial maze (Narita et al., 2010). Exposure on E15 inhibits vasculogenesis and alters cortical and hippocampal morphology (Fan et al., 2008). Furthermore, daily maternal injection of rats from E7 to E18 yields adult offspring with altered learning and memory as measured by increased errors and latency in the Cincinnati water maze (Vorhees et al., 2001). Clearly, much more could be done with this model to establish its relevance for autism.
Because VPA retains its teratogenicity in rodents, its administration during the time of neural tube closure has proven useful as a rodent model. VPA was first introduced in the 1960s as an anticonvulsant and later as a mood-stabilizing drug for treatment of epilepsy and bipolar disorder (Markram et al., 2007). Like thalidomide, use of VPA during early human pregnancy significantly elevates the incidence of autism and the development of craniofacial defects in exposed offspring. Both case and epidemiological studies have confirmed the association between fetal valproate syndrome and autism (Hyman et al., 2006; Fan et al., 2008). Although women who are prescribed VPA for treatment of epilepsy often take the drug throughout pregnancy, it is unclear whether brain regions other than the brain stem are vulnerable to VPA insult at later stages of development (Rinaldi et al., 2007a).
In animal studies, a single injection of VPA in a pregnant rat results in striking neuropathology and behavioral abnormalities. Offspring of rats injected with VPA show brain defects resembling those sometimes found in autism, including reduced number of motor nuclei and PCs (Schneider & Przewlocki, 2005), hyperserotonemia, and disorganized migration of 5-HT neurons in the dorsal raphe nuclei (Miyazaki et al., 2005). Fetuses from VPA-injected mothers display hypoplasia of the cortical plate, abnormal migration of dopaminergic and serotonergic neurons, and abnormal pons pathology (Kuwagata et al., 2009). VPA is a histone deacetylase inhibitor that is thought to impede neuronal differentiation and migration by interfering with the sonic hedgehog signaling pathway.
Interestingly, offspring of rats injected with VPA on E12.5 develop behavioral abnormalities that appear before puberty, a feature that distinguishes this model from behavioral changes seen in schizophrenia (Schneider & Przewlocki, 2005). VPA offspring display lower sensitivity to pain and higher sensitivity to nonpainful sensory stimuli, which parallels reported changes in endogenous opioid systems in some autistic patients. These offspring also exhibit impaired sensorimotor gating as measured by acoustic PPI, elevated anxiety as evidenced by decreased open field exploration, increased stereotypic/repetitive activity, decreased social interaction, impaired reversal learning, altered eyeblink conditioning patterns, and enhanced fear memory processing, all of which are consistent with results in autistic children (Stanton et al., 2007; Murawski et al., 2008; Markram et al., 2008; Dufour-Rainfray et al., 2010; Roullet et al., 2010) (Table 52-1). A sexual dimorphism has been reported for some of these parameters, with abnormalities seen only in male offspring, which is also consistent with the very significant male bias in autism (Schneider et al., 2008). It will also be interesting to look for communication deficits (USVs) in this model.
Table 52–1. Behavioral assays used in rodent models of autistic features
three-chambered cage with inanimate object versus social object (mouse)
time spent in each chamber; number of approaches
preference for social novelty
three-chambered cage with familiar mouse versus unfamiliar mouse
time spent in each chamber; number of approaches
empty cage; pups are briefly isolated from mothers
number of calls, frequency of calls, type of call
learning and memory
Cincinnati water maze (multiple T maze)
maze design consisting of nine interlinked T-units submerged in water; mice are trained to swim to the escape platform
latency to find platform; time spent swimming in the trained quadrant of the pool as compared to time spent in the other quadrants
Morris water maze
circular pool of opaque water; mice are initially trained to swim to visible platform and then to submerged hidden platform
latency to find platform; time spent swimming in the trained quadrant as compared to time spent in the other three quadrants
chamber with tone generator for administration of a series of tones (conditioned stimulus, CS) followed by a periorbital shock (unconditioned stimulus)
occurrence of eyeblink as measured by EMG eyeblink signal (conditioned response, CR); amplitude of CR; latency between CS and onset of CR; latency between CS and peak of CR
novel object exploration
brightly lit open arena; in first trial, mice are exposed to two objects; in the second trial, one of the two objects is exchanged for a novel object
investigation of novel object; time spent with the novel object
novel location exploration
brightly lit open arena; in the first trial, mice are exposed to two objects; in the second trial, one of the two objects is moved to a new location
investigation of moved object; time spent with moved object
chamber with tone generator for administration of a series of tones followed by an adversive stimulus (mild foot shock)
whole body flinch amplitude; freezing in context environment and after tonal cues
acoustic prepulse inhibition
cage with tone generator for administration of a series of prepulse tones followed by startle stimulus
whole body flinch amplitude; freezing
open field exploration
brightly lit open arena
center duration, number of center entries, total distance traveled, horizontal activity, vertical activity (rearing)
brightly lit open arena
total distance traveled, horizontal activity, vertical activity (rearing)
Electrophysiological studies indicate that offspring of VPA-treated mothers exhibit abnormal microcircuit connectivity in the neocortex and amygdala. Exposure to VPA results in overexpression of CaMKII and the NR2A and NR2B NMDA receptor subunits in the neocortex (Rinaldi et al., 2007b). These observations are consistent with observed increases in NMDA receptor-mediated synaptic transmission and enhanced postsynaptic long-term potentiation in neocortical pyramidal neurons. Adult VPA offspring also show increased connection probability of layer 5 pyramidal cells but decreased excitability and decreased putative pyramidal cell synaptic contacts (Rinaldi et al., 2008). These results relate to MRI studies showing impaired long-range functional connectivity in autistic individuals (Just et al., 2004).
Recordings from neurons in the lateral amygdaloid nucleus demonstrate hyper-reactivity to electrical stimulation, elevated long-term potentiation and impaired stimulus inhibition that may contribute to the deficient fear extinction and high anxiety seen in VPA offspring (Markram et al., 2008). These results suggest molecular and synaptic alterations in VPA mice that are relevant for the alterations in amygdala morphology observed in autism (Amaral et al., 2008). Dysfunction in the amygdala may contribute to the decreased social interaction and/or abnormal fear processing characteristic of autistic pathology (Markram et al., 2008). While deficits in social play and exploration have been reported in VPA rodent offspring (Schneider et al., 2008), an important gap in the behavioral analysis of social interaction is in the analysis of social preference and USVs.
Although the mechanisms underlying the effects of prenatal VPA on fetal brain development are largely unknown, neural inflammation and gene regulation could be involved. Immunological alterations have been reported in offspring of VPA-treated mice (Schneider et al., 2008; Bennett et al., 2000), and in vitro studies indicate that VPA promotes astrocyte proliferation, inhibits microglial and macrophage activation, and induces microglial apoptosis (Peng et al., 2005; Dragunow et al., 2006). This is consistent with the finding that VPA can regulate epigenetic modifications through three mechanisms: inhibiting histone deacetylases, enhancing histone acetylation, and promoting demethylase activity (Chen et al., 2007). The ability of VPA to alter HOX gene expression is of particular interest, as HOXa1 is expressed during the time of neural tube closure and regulates development of the facial nucleus and superior olive (c.f., Finnell et al., 2002). Moreover, VPA treatment may actually promote neurogenesis of GABAergic neurons and facilitate neurite outgrowth (Dragunow et al., 2006). These neuroprotective effects occur after chronic VPA treatment rather than the acute exposure administered in the maternal VPA model, however (Hao et al., 2004; Ren et al., 2004).
Although maternal VPA and thalidomide exposure are responsible for only a small fraction of autism cases, the extremely high risk for autism in the offspring provides proof-of-principle for environmental influences on autism incidence. Moreover, the similarities in neuropathology and behavior between the rodent models and human autism support the utility of environment-based models for defining relevant pathways of developmental dysregulation. It will be important to extend the VPA model to mice carrying genetic variants associated with increased risk for autism, which would provide a test of the gene x environment paradigm. Interestingly, prenatal VPA exposure has been linked to altered expression of neuroligin3, a genetic susceptibility factor for autism (Kolozsi et al., 2009).
Maternal infection is an environmental risk factor for the development of several neuropsychiatric disorders in the offspring. As is the case for schizophrenia (Patterson, 2007; Brown & Derkits, 2010), maternal viral infection is linked to higher incidence of autism by clinical, epidemiological, and case studies. Early evidence for this came from the 1964 rubella pandemic, in which the incidence of autistic features was increased more than 200-fold in the offspring of infected mothers (Chess, 1977). Case studies have linked autism to several other prenatal viral infections, including varicella, rubeola, and cytomegalovirus (Ciaranello & Ciaranello, 1995). Bacterial and protozoan infections have also been associated with autism (Nicolson et al., 2007; Bransfield et al., 2008). The most compelling evidence linking maternal infection with autism comes from a very large study utilizing the Danish Medical Birth Register. An examination of over 10,000 autism cases found a very significant association with maternal viral infection in the first trimester (Atladottir et al., 2010). In sum, the diversity of micro-organisms implicated in autism, along with the fact that several of these infections do not involve direct transmission into the fetus, suggests that the maternal immune response, rather than microbial pathogenesis, is responsible for increasing the risk for autism in the offspring (Figure 52-2). Animal models of maternal infection further support the idea that maternal immune activation (MIA) and the production of pro-inflammatory cytokines are what unite the various types of maternal infection as risk factors for autism. There are three primary rodent models for MIA: maternal influenza infection, poly (I:C) injection, and lipopolysaccharide (LPS) injection.
Pregnant mice intranasally infected with influenza yield offspring with behavioral and neuropathological abnormalities that parallel those seen in autism. Abnormal behaviors include heightened anxiety during open-field exploration, deficient PPI, decreased novel object exploration, and reduced social interaction (Shi et al., 2003). These offspring display spatially selective PC loss in lobules VI and VII (Figure 52-3) (Shi et al., 2009), which is a common neuropathology in autism (Palmen et al., 2004; Amaral et al., 2008). There is also macrocephaly, delayed cerebellar granule cell migration, reduced Reelin immunoreactivity in the cortex, thinning of the neocortex and hippocampus, and altered expression of neuronal nitric oxide synthase and synaptosome-associated protein-25 (Fatemi et al., 2002; Shi et al., 2009). Infection on E16 or E18 causes altered expression of several genes associated with autism, white matter thinning in the corpus callosum, widespread brain atrophy, and altered levels of cerebellar 5-HT but not dopamine (Fatemi et al., 2008, 2009; Winter et al., 2008).
Because maternal influenza infection is largely confined to the respiratory tract, it is unlikely that these neurological defects are caused by direct viral infection of the fetus. There are, however, conflicting reports as to whether viral mRNA or protein is present in fetal tissues (Aronsson et al., 2002; Shi et al., 2005). Nonetheless, the fact that stimulating the maternal immune system with poly (I:C) (mimicking viral infection) and LPS (mimicking bacterial infection) causes neuropathogical and behavioral defects in the offspring similar to those seen with maternal influenza infection supports the idea that MIA is the causative event, as no pathogen is required. Poly (I:C) is a synthetic, double-stranded RNA that generates an antiviral immune response in the absence of virus. Depending on the dosage, mode of injection (intraperitoneal or intravenous) and timing of maternal poly (I:C) administration, offspring display deficits in PPI, latent inhibition, open field exploration, working memory, social interaction and USVs, while reversal learning and amphetamine-induced locomotion are enhanced (Shi et al., 2003; Zuckerman et al., 2003, 2005; Lee et al., 2007; Meyer et al., 2007; Smith et al., 2007; Winter et al., 2009; Malkova & Patterson, 2010). A single poly (I:C) injection also causes histopathological changes similar to those seen in autism, including increased GABAA receptor, spatially-restricted reduction in PCs, and delayed myelination, and decreased cortical neurogenesis (Nyffeler et al., 2006; Shi et al., 2009; Makinodan et al, 2008; De Miranda et al., 2010). A cardinal pathology in schizophrenia, enlarged lateral ventricles, is also observed (Li et al., 2009; Piontkewitz, Assaf, & Weiner, 2009). In addition, there is evidence of physiological abnormalities in the hippocampus. In slices from adult offspring of poly (I:C)-treated mothers, oscillations in CA1 are less rhythmic than in controls, and CA1 pyramidal neurons display reduced frequency and increased amplitude of miniature excitatory postsynaptic currents. Differing results have been reported regarding a deficit in long term potentiation (Ito et al., 2010; Oh-Nishi et al., 2010). Interestingly, the specific component of the temporoammonic pathway that mediates object-related information displays significantly increased sensitivity to dopamine (Lowe et al., 2009; Ito et al., 2010). There are a few studies describing abnormal dopamine levels in autism (Previc, 2007), and a variety of changes in dopamine are found in the maternal poly (I:C) model (Zuckerman et al., 2003; Ozawa et al., 2006; Meyer et al., 2008a). However, whether dysregulation of the dopaminergic system is an important feature of autism is unknown. Dopamine pathology is very important in schizophrenia, where maternal infection is also a risk factor. Another finding consistent with both schizophrenia and autism is a disruption in long-range synchrony of neuronal firing. Adult MIA offspring display significant reduction in medial prefrontal cortex-hippocampal EEG coherence (Dickerson, Wolff & Bilkey, 2010).
Further supporting the role of MIA in altering fetal brain development is the use of maternal LPS injection to simulate bacterial infection. Although poly (I:C) and LPS act through different toll-like receptors, their effects on the behavior and brain pathology in offspring often overlap. For example, a single injection of LPS in a pregnant rat yields offspring with elevated anxiety, aberrant social behavior, reduced play behavior and USVs, reduced PPI, enhanced amphetamine-induced locomotion, and abnormal learning and memory (Borrell et al., 2002; Fortier et al., 2004; Golan et al., 2005; Hava et al., 2006; Basta-Kaim et al., 2010; Baharnoori et al., 2010; Hao et al., 2010; Kirsten et al., 2010), many of which parallel behaviors seen in autism. There is also evidence of hyperactivity in the hypothalamus-pituitary-adrenal axis in the LPS offspring, and some of the abnormal behaviors can be reversed by anti-psychotic drug treatment (Basta-Kaim et al., 2010), as is the case for the poly (I:C) offspring. Recall that maternal infection is a risk factor for schizophrenia as well as autism.
Histological findings include smaller, more densely packed neurons in the hippocampus, increased numbers of pyknotic cells in the cortex, fewer tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra, and increased TH+ cells in the nucleus accumbens (Golan et al., 2005; Ling et al., 2004; Borrell et al., 2002). Further studies indicate that changes in dendritic length, dendritic branching, spine structure, and spine density in the medial prefrontal cortex and hippocampus, suggesting dysregulated neuronal connections formed during embryogenesis (Baharnoori et al., 2008). Some of these effects, including increased cell density and limited dendritic arbors in the hippocampus, have been found in MRI and post mortem brain studies in autism (Amaral et al., 2008). Electrophysiological recordings reveal reduced synaptic input to CA1 of the hippocampus, heightened excitability of pyramidal neurons, enhanced postsynaptic glutamatergic response, and impaired NMDA-induced synaptic plasticity (Lowe et al., 2008; Lante et al., 2008). Interestingly, many of these effects are prevented by pretreatment of pregnant rats with N-acetyl-cysteine (Lante et al., 2008), which increases calcium influx when binding to glutamate receptors in combination with the transmitter. Brain imaging studies of the hippocampus and of particular neurotransmitter systems in autism have yielded inconsistent results, so no definite statement can be made about their exact roles in autism (Palmen et al., 2004).
In addition to the behavioral deficits and neuropathology, the MIA models also share with autism dysregulation of immune status in the brain. Post mortem brain and cerebrospinal fluid samples from autistic individuals exhibit marked astrogliosis, microglial activation, dysregulation of immune-related genes, and high levels of pro-inflammatory cytokines and chemokines (Vargas et al., 2005; Garbett et al., 2008; Chez et al., 2007; Tetreault et al., 2009; Patterson, 2009). Although LPS itself does not cross the placental barrier, maternal LPS injections yield offspring with MHC II induction along with increased GFAP and microglial staining in various adult (Borrell 2002; Ling et al., 2004) and fetal (Paintlia et al., 2004) brain regions. While several cytokines are elevated in the placenta and amniotic fluid after MIA, mRNA transcripts for a number of cytokines are also elevated in the fetal brain following maternal LPS or poly (I:C) (Urakubo et al., 2001; Cai et al., 2000; Paintlia et al., 2004; Liverman et al., 2006; Golan et al., 2005; Meyer et al., 2008b; Elovitz et al., 2006; Hsiao & Patterson, 2010). The importance of cytokines as soluble mediators of the effects of MIA on fetal brain development was demonstrated using cytokine knockout (KO) mice and mice injected with recombinant cytokines or cytokine-neutralizing antibodies. Interleukin (IL)-6 is necessary and sufficient for mediating the effects of MIA on the development of neurological, behavioral, and transcriptional changes in poly (I:C)-exposed offspring (Figure 52-2; Samuelsson et al., 2006; Smith et al., 2007). In a converse approach, overexpression of the anti-inflammatory cytokine IL-10 suppresses the effects of maternal poly (I:C) on the fetus (Meyer et al., 2008c). Perturbation of IL-10, IL-1, or TNFα can also significantly influence the outcome of MIA in the LPS MIA model (Girard et al., 2010; reviewed in Patterson, 2011).
How cytokines induced by MIA alter the course of fetal brain development is largely unknown. The most obvious possibility is by direct action on the developing brain, as both cytokines and chemokines are key modulators of astrogliosis, neurogenesis, microglial activation, and synaptic pruning (Bauer et al., 2007; Deverman & Patterson, 2009), and some maternal cytokines have been reported to cross the placenta (Dahlgren et al., 2006; Zaretsky et al., 2004). A second possibility is that MIA alters the endocrine function and/or the immunological state of the placenta. In fact, poly (I:C) MIA increases maternally-derived IL-6 protein as well as IL-6 mRNA in the placenta. Such placentas exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Moreover, maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway in the placenta, which parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor axis (Hsiao & Patterson, 2010). Such endocrine changes could affect the development of the fetal brain and immune system, with permanent consequences. It is notable that a greater occurrence of placental trophoblast inclusions is observed in placental tissue from births of children who develop autism spectrum disorder compared to non-ASD controls (Anderson et al., 2007). Moreover, chorioamnionitis and other obstetric complications are significantly associated with socialization and communication deficitis in autistic infants (Limperopoulos, 2008).
In this context, it is of interest that several studies have reported that the sera of some mothers of autistic children contain antibodies that bind fetal human, monkey, or rat brain antigens (Zimmerman et al., 2007; Braunschweig et al., 2008; Martin et al., 2008). Most relevant to this review is the further finding that injection of such maternal sera into pregnant mice (Dalton et al., 2003) or purified maternal IgG into pregnant Rhesus monkeys (Martin et al., 2008) yields offspring with several behavioral abnormalities, including hyperactivity and stereotopies in the case of the monkeys. That something is different about the immune system of in the mothers of autistic offspring is further supported by the observation that these mothers are more likely to have a history of autoimmune disease or asthma (e.g., Altadottir et al., 2009). There is also evidence that the peripheral immune system of autistic subjects is abnormal (Pardo & Eberhart, 2007; Enstrom, Van de Water, & Ashwood, 2009). In that light it is interesting that, compared to controls, CD4+ T cells from the spleen and mesenteric lymph nodes of adult mouse MIA offspring display significantly elevated IL-6 and IL-17 responses to in vitro stimulation (Hsiao et al., 2010; Mandal et al., 2010). Furthermore, adult MIA offspring display reduced T cell responses to CNS-specific antigens, despite elevated proliferation of nonspecific T cells (Cardon et al., 2009).
Although it is commonly stated that autism can result from an environmental stimulus acting on a susceptible genetic background, there is little support for this hypothesis thus far. Thus, it is of interest that mice heterozygous for the tuberous sclerosis 2 (TSC2) gene display a social interaction deficit only when they are born to mothers treated with poly (I:C) (Ehninger et al., 2010). That is, this deficit is most severe when the MIA environmental risk factor is combined with a genetic defect that, in humans, also carries a very high risk for ASD. In addition, there is an excess of TSC-ASD individuals born during the peak influenza season, an association that is not seen for TSC individuals not displaying ASD symptoms (Ehninger et al., 2010).
Although there is currently no convincing evidence that postnatal vaccination is a cause of autism, the occasional coincidence in the timing of routine childhood immunizations with the appearance of autistic symptoms continues to fuel public concern. The measles-mumps-rubella (MMR) vaccine is of particular interest because of the use of live, attenuated virus, but there are currently no rodent models for the effects of MMR on neural development. Moreover, many epidemiological studies have failed to substantiate a connection between MMR vaccination and autism (DeStefano, 2007).
There has been investigation of the effects of thimerosal-containing vaccines (TCVs) on neurodevelopment in rodents. Increased mercury burden from this sodium ethylmercurithiosalicylate preservative is of concern because of known neurotoxic properties of methylmercurials. One study reported that immunogenetic factors can render mice susceptible to thimerosal-induced neurotoxicity (Hornig et al., 2004). The autoimmune-prone SJL/J (H-2s) strain developed neuropathology and abnormal behavior. However, a recent study failed to replicate the histological and behavioral results (Berman et al., 2008). This latter paper is consistent with several epidemiological studies failing to support a link between thimerosal and autism (Andrews et al., 2004; Schechter & Grether, 2008; Gerber & Offit, 2008 Price et al., 2010).
The β2 adrenergic receptor is expressed early in fetal brain development, and its activation affects cell proliferation and differentiation. Terbutaline is a selective β2 adrenergic receptor agonist that is used to relax uterine smooth muscle to prevent premature labor and birth. A study of dizygotic twins found an increased rate of concordance for autism if the mother was given terbutaline for 2 weeks (Conners et al., 2005). Further implicating the β2 adrenergic receptor is the finding that certain functional variants of this gene are associated with increased risk for autism (Cheslack-Postava et al., 2007). In modeling this risk factor in rats, neonates are given subcutaneous injections of terbutaline daily, from postnatal days 2 through 5, a time meant to mimic the stage of human brain development at which the drug is given. A significant deficit in PCs was found, but no mention of any spatial restriction of this change was made. Histological changes were reported in the hippocampus and somatosensory cortex as well, including microglial activation in cortex and cerebellum (Rhodes et al., 2004; Zerrate et al., 2007). Also of interest in terms of autism is a finding of increased 5-HT turnover (Slotkin & Seidler, 2007). Behavioral analysis of this model is somewhat disappointing thus far, with female-specific hyperactivity and no change in PPI (Zerrate et al., 2007).
X-Linked and Autosomal Lesions
Fmr1 Knockout Mice
Fragile X Syndrome (FXS) is an X-linked condition that is the leading genetic cause of mental retardation (Hatton et al., 2006). It is caused by the loss of expression of FMRP, an mRNA-binding protein that is highly expressed in hippocampal and cortical synapses, where it regulates translation of its target mRNAs and thus plays a key role in protein synthesis-dependent functions (Bassell & Warren, 2008). It is estimated that 90% of FXS patients present some autistic-like behaviors, and that 15% to 33% meet the full diagnostic criteria of autism (Cohen et al., 1988; Bailey et al., 1998). Overall, FXS accounts for about 5% of the autistic population (Li et al., 1993). Fmr1 KO mice display some anatomical features of FXS, such as macro-orchidism and abnormal dendritic development and morphology (The Dutch-Belgian Fragile X Consortium, 1994) and spines are altered in idiopathic autism (Zoghbi, 2003). These mice also display some core behavioral features relevant to autism, including impaired social interaction (McNaughton et al., 2008) and repetitive behaviors. Whether they display learning and memory deficits is unclear (Dobkin et al., 2000; Frankland et al., 2004) and whether they show other autism-related symptoms such as anxiety and hyperactivity depends on the genetic background (Bernardet & Crusio, 2006). The observations that both cognitive performance and behaviors relevant to autistic traits are affected by genetic background is of interest given the genetic variability in humans and the phenotypic heterogeneity in FXS. Although overall resemblance to autism is partial, the presence of two core features of autism indicates that molecular investigation of Fmr1 KO mice may further our understanding of the genetic etiology of FXS and autistic traits.
The signaling pathways for metabotropic glutamate receptor 5 (mGluR-5) and PAK, a kinase involved in actin remodeling and regulation of synapse structure, represent two plausible therapeutic targets for FXS and autism. A 50% reduction of mGluR-5 expression in Fmr1 KO mice normalizes dendrite morphology, seizure susceptibility, and inhibitory avoidance extinction (Dolen et al., 2007) (Table 52-2). This supports the mGluR theory, which posits that upregulation of group I mGluR leads to exaggerated protein synthesis-dependent functions, such as long-term depression, and therefore underlies the neuropathology and behavioral traits associated with FXS (Bear, Huber, & Warren, 2004). Interestingly, postnatal inhibition of PAK in the forebrain of Fmr1 KO mice normalizes dendrite morphology and restores locomotion, repetitive behavior, and anxiety (Hayashi et al., 2007). In addition, in a Drosophila model, treatment with mGluR antagonists or protein synthesis inhibitors in adulthood can partially restore deficits in courtship behavior and improve memory (McBride et al., 2005; Bolduc et al., 2008). Two small, open label human trials based on these findings yielded promising results (Berry-Kravis et al., 2008, 2009; Paribello et al., 2010), supporting the use of FXS animal models for preclinical purposes.
Table 52–2. Amelioration (orange) or rescue (yellow) of some features of the autism-like phenotype in double mouse mutants phenotypic improvements or reversals indicate functional (direct or indirect) interactions between the targeted genes, whereas persistence of one phenotype (blue) suggests that additional genes contribute to the full phenotype. Investigation of genetic interactions provides insight into the molecular pathways underlying particular facets of autism, and may suggest novel therapeutic targets
Mouse Mutant Relevant to Autism
Rescuer Mouse Mutant
Phenotype of the Double Mutant
FMR1 knockout (FMR1 KO) mice
Dominant negative PAK transgenic mice
40% inhibition of the catalytic activity of PAK
(Hayashi et al., 2007)
Hyperactivity, stereotypy, and hypoanxiety in open field are rescued
Spine density partially restored
Memory deficits restored
Spine length comparable to WT
Reduced cortical LTP is rescued
Grm5 mutant mice
50% reduction in mGluR5 expression
(Dolen et al., 2007)
Exaggerated inhibitory avoidance extinction rescued
Spine density comparable to WT
Ocular dominance plasticity rescued
Increased protein synthesis in the hippocampus is prevented
Growth increase at P30 rescued
Audiogenic seizures attenuated
Macroorchidism not rescued
Germline Mecp2 mutant
Conditional BDNF-over-expressing transgenic mice
Increase in BDNF expression
(Chang et al., 2006)
Improvement in the running wheel assay (locomotor function)
Neuronal activity indistinguishable from WT
Extension of the lifespan
Modest increase in brain weight
Angelman syndrome mutant
CaMKII-T305V/T306A mutant mice
Mutations in CaMKII that prevent its auto-phosphorylation
(Van Woerden et al., 2007)
Rotarod performance indistinguishable from WT
Absence of audiogenic seizures
Increase in body weight rescued
75% reduction of propensity for seizures
Context-dependant memory restored (hippocampal learning deficit rescued)
Long-term potentiation rescued
Improved water maze performance
Methyl-CpG-Binding Protein-Null, Mutant, and Overexpressing Mice
Rett syndrome is another X-linked disorder that causes mental retardation, primarily affecting females. It is estimated that 95% of Rett syndrome cases are caused by mutations in the methyl-CpG-binding protein (MECP2) gene (Chahrour & Zoghbi, 2007), leading to deficiency in this global transcriptional regulator, whose targets include BDNF. During the regression phase of the disease, affected girls display autistic-like behaviors, such as stereotypies as well as reduced social contact and communication. Association between MECP2 variants and autism have also been reported (Loat et al., 2008). Both Mecp2-null mice, and mice in which Mecp2 is deleted in mature neurons only, exhibit a neurological phenotype consistent with Rett, including hypoactivity, ataxic gait, tremor, limb-clasping, and reduced brain size with smaller neuronal cell bodies in cortex and hippocampus (Chen et al., 2001; Guy et al., 2001). BDNF levels are also reduced in comparison to wild-type (WT) animals, and deletion or over-expression of Bdnf in the Mecp2 mutant brain either accelerates or delays the onset of the symptoms, suggesting a functional interaction between Mecp2 and BDNF in vivo (Chang et al., 2006). Male mice that carry the truncating mutation, Mecp2308/y, a common variant observed in Rett patients, display a milder Rett-like phenotype (Shahbazian et al., 2002). Increased synaptic transmission and impaired LTP induction is observed in the mutant mice, whereas spine morphology, BDNF levels, and synaptic biochemical composition are not altered. Behavioral deficits in these mice include enhanced anxiety in the open field, reduced nest-building, and aberrant social interactions. Genetic background modifies performance in the Morris water maze, latent inhibition, and long-term memory tasks (Moretti et al., 2005; Moretti et al., 2006). Mice over-expressing Mecp2 also develop a progressive neurological disorder with, surprisingly, an enhancement in synaptic plasticity, motor and contextual learning skills between age 10 and 20 weeks, and, at an older age, hypoactivity, seizures, and abnormal forelimb-clasping, all of which are reminiscent of human Rett syndrome (Collins et al., 2004). These results with the various Mecp2 mouse models indicate that this gene must be tightly regulated under normal conditions. These mice should aid in the search for genes that are regulated by Mecp2 (Chahrour et al., 2008) and possibly the various behavioral abnormalities. These mice are also providing reason for optimism regarding the testing of potential treatments for Rett syndrome. In a conditional KO model, it was shown that restoring Mecp2 expression in immature or even in mature mice results in reversal of the disease phenotype, as measured by behavioral and electrophysiological tests (Guy et al., 2007). Thus, despite the fact that Mecp2 function was disrupted during fetal and postnatal development, the disease symptoms can be reversed. In one test of a potential treatment, administration of an active peptide fragment of insulin-like growth factor 1 to Mecp2 mutant mice extends life span, improves locomotor, heart and breathing functions, and stabilizes a measure of cortical plasticity (Tropea et al., 2009). Such results provide proof-of-principle that these mice can be used to screen candidate treatments of autism-related disorders.
Angelman and Prader-Willi Syndromes
Loss of function of maternal or paternal genes in the imprinted chromosomal region 15q11-q13 causes Angelman Syndrome and Prader-Willi Syndrome (PWS), respectively. Although clinically distinct, both syndromes are behavioral disorders presenting with some autistic traits as well as other diverse symptoms (Veltman et al., 2005). Linkage studies have also associated the 15q11-q13 locus with autism, and maternal duplications of this region account for rare cases of autism (Wassink & Piven, 2000). 70% of Angelman Syndrome patients carry large maternal deletions of 15q11-q13, and display a severe phenotype; yet, mutations in a single gene, UBE3A, are sufficient to cause major clinical manifestations of the syndrome. By contrast, PWS is clearly a multigenic syndrome involving 10 imprinted genes, whose individual significance in the etiology of the disorder is not yet fully clarified (Nicholls & Knepper, 2001). UBE3A encodes E6-AP, an enzyme that has ubiquitin protein ligase and transcriptional coactivator activities (Nawaz et al., 1999). Two different KO mouse strains with maternally inherited mutations in Ube3a display a phenotype consistent with human Angelman Syndrome: motor dysfunction, propensity for seizures, defective learning and memory, and abnormal electroencephalograms (Jiang et al., 1998; Miura et al., 2002). These mice also display deficits in hippocampal LTP and decreased hippocampal CaMKII activity, which may contribute to learning problems in Angelman Syndrome (Weeber et al., 2003). When crossed to mice carrying a mutation in CaMKII that prevents its autophosphorylation, the double mutants no longer exhibit the Angelman Syndrome phenotype (van Woerden et al., 2007). This suggests that increased inhibitory autophosphorylation may provide a molecular basis for deficits in LTP, motor coordination, and seizure propensity. Studies of another Angelman Syndrome mouse model, the Ube3aYFP knock-in (KI) reporter mouse, reveal that E6-AP is found in synapses and the nucleus (Dindot et al., 2008). These mice display decreased spine density, an interesting finding because altered spine morphology is observed in Rett and FXS patients, as well as in Fmr1 KO mice (Kaufmann & Moser, 2000). Thus, the neuropathology in this KI suggests that E6-AP could play a role in spine development and synaptic plasticity. It is relevant that loss of UBE3A activity or its overexpression in Drosophila reduces dendritic branching and affects dendrite morphogenesis (Lu et al., 2009). It remains to be determined whether similar neuropathology is present in the KO mouse lines and Angelman Syndrome patients and whether it contributes to cognitive dysfunction and behavioral abnormalities.
More recently, mutant mice carrying a large maternal deletion from Ube3a to Gabrb3 were generated (Jiang et al., 2010). Similar to the Ube3a KO mice, these mutants display increased spontaneous seizure activity, abnormal electroencephalograms, as well as impairments in learning and memory. Additional behavioral tests reveal that they display anxiety traits in the light-dark box, but no difference in pain sensitivity or in PPI. Mutant newborn pups emit more USVs than control mice. This latter observation is of interest, since Angelman syndrome patients show a happy disposition that is currently interpreted as increased signaling behavior. Relevance to autism is also possible, as increased USVs have been reported in Mecp2 mutant and BTBR pups. However, one would expect to see fewer USVs in an autism model, given the deficits in communication in ASD. Comparative studies of the various mouse models of Angelman syndrome should yield new insights into the contribution of additional, maternally imprinted genes of this region, or biallelically expressed genes such as Gabrb3 or Atp10a. Mouse models for PWS with deletion of the corresponding murine imprinted locus have been generated, but early postnatal lethality has precluded behavioral characterization (Yang et al., 1998). Among the mice engineered to carry a mutation in one candidate gene of the imprinted region, Necdin (Ndn), paternally-deficient mice display some behavioral traits reminiscent of PWS, such as skin-scraping, improved performance in Morris water maze, and reduced numbers of hypothalamic oxytocin- and LHRH-producing neurons (Muscatelli et al., 2000). Serotonergic alterations are also observed in these mice and are linked to respiratory deficiency (Zanella et al., 2008). All these findings might be relevant to autism, because repetitive self-injury, enhanced visual-spatial skills, oxytocin abnormalities, and alterations in serotonin levels have been described in autism. As with Angelman syndrome mice, Necdin mutant mice require further behavioral characterization.
Pten Mutant Mice
Phosphatase and tensin homolog on chromosome 10, PTEN, is a tumor suppressor that negatively regulates phosphatidylinositol 3-kinase PI3K/Akt signaling, a pathway that promotes cell growth, proliferation, and survival. Germline mutations in PTEN cause Cowden and Bannayan–Riley–Ruvalcaba syndromes (CS and BRRS, respectively). CS and BRRS are characterized by benign and malignant tumors in multiple organs as well as brain disorders such as macrocephaly, mental retardation, and seizure. Association between these syndromes—particularly CS—and autism has occasionally been reported (Zori et al., 1998; Goffin et al., 2001; Pilarski & Eng, 2004). Moreover, genetic screening identified PTEN mutations in a subset of autistic individuals who display macrocephaly (Butler et al., 2005; Buxbaum et al., 2007), an anatomical anomaly also present in 15% to 20% of autistic patients (Lainhart et al., 2006). Of particular interest is the mouse strain Nse-cre-PtenloxP/loxP, in which a Pten deletion is restricted to differentiated neurons in the cerebral cortex and hippocampus (Kwon et al., 2006). These mutants develop forebrain macrocephaly resulting from neuronal hypertrophy in the cortex and hippocampus. In addition, analysis of the hippocampus shows increased dendritic and axonal growth, ectopic positioning of axons and dendrites of granule neurons and elevated synapse number.
Abnormalities in Pten-deleted neurons correlate with enhanced levels of phosphorylated Akt and its downstream effectors, mTOR and S6. Components of the mTOR/S6K/S6 pathway are present in dendrites, where they are involved in the regulation of protein synthesis. Protein synthesis in dendrites is believed to modulate synapse morphology and function and thus is involved in synapse plasticity. These mice display behaviors reminiscent of autism, such as deficits in social interaction, exaggerated responses to sensory stimuli, decreased PPI (but only at one prepulse stimulus intensity), anxiety-like behavior in the open field, and learning deficits in the Morris water maze. However, no impairments in fear conditioning, elevated plus maze, or motor activity are observed. Increased spine density and social deficits are also observed in the Fmr1 KO. In this context, it is relevant that ribosomal S6 kinase (S6K1), a component of the mTOR/PI3K signaling cascade, was recently identified as a major Fmrp kinase (Narayanan et al., 2008). Because the phosphorylation status of FMRP may govern translational regulation of its target mRNAs, upstream modulators of the mTOR/PI3K pathway such as PTEN may modulate synaptic function by affecting FMRP phosphorylation status (Bassell & Warren, 2008). Thus, FMRP phosphorylation may be affected in CS, BRRS, and also tuberous sclerosis (TSC), another human disorder associated with autism, caused by mutations in the TSC1/2 complex. Indeed, hamartin and tuberin, the gene products of TSC1 and TSC2, can inhibit mTOR (Yates, 2006). Moreover, mTOR signaling is dysregulated in the Fmrp-deficient mouse (Sharma et al., 2010). Taken together, these data support the hypothesis that synaptic alteration may underlie autistic-like behaviors (Zoghbi, 2003) and highlight the mTOR pathway as a key regulator of synaptic function. In addition, as in the case of the Mecp2 mice, the Tsc2+/- mouse model responds to treatment in adulthood. Brief administration of the mTOR inhibitor rapamycin rescues synaptic plasticity and the behavioral deficits in the TSC model (Ehninger et al., 2009). Moreover, early phase clinical trials suggest that cognitive features of TSC may be reversible in adult humans (De Vries, 2010).
Autism Candidate Genes
Neuroligins 3 and 4
Recent findings in autism genetics have revealed several, rare causal variants that are associated with ASD (Betancur, Sakurai, & Buxbaum, 2009). Neuroligins (NLGNs) constitute a family of transmembrane postsynaptic proteins, which, together with their presynaptic and intracellular binding partners, the β-neurexins and SHANK3, respectively, play a key role in synaptic maturation and transmission. NLGN3 and -4 were identified in two X-chromosome loci previously associated with ASDs (Jamain et al., 2003). Thus far, one missense mutation in NLGN3 and four missense and two nonsense mutations in NLGN4 have been identified in a very small number of individuals with ASDs (Jamain et al., 2003; Laumonnier et al., 2004; Yan et al., 2005), supporting the hypothesis that synaptic dysfunction is important in ASDs. Mutations in neurexin and SHANK3 are also found in ASD probands, but whether they are involved in ASD etiology is controversial (Sudhof, 2008). There is currently no KO for Shank3, but a KO for Shank1, the closest relative to Shank3, was recently created. These mutants display morphological alterations in hippocampal neurons that are associated with a reduction in basal synaptic transmission, but no change in several other electrophysiological parameters (LTP, LTD, and L-LTP). Behaviorally, Shank1 KO mice exhibit increased anxiety, impaired contextual fear memory, and, surprisingly, enhanced performance in a spatial learning task but impaired memory retention of that task (Hung et al., 2008). Additional behavioral tasks relevant to the three core symptoms have yet to be reported.
Results with Nlgn3 and -4 mutant mice confirm the functional significance of NLGNs in synaptic function. A Nlgn3 KI mouse was engineered with a point mutation in the endogenous mouse gene that is identical to the relevant human NLGN-3 gene (Tabuchi et al., 2007). These mice display increased inhibitory synaptic transmission without a change in excitatory transmission, a phenotype not observed in Nlgn3 KO mice, emphasizing the disparity between missense and nonsense mutations. It will be of interest to characterize the behavior of the KO mice to check for differential phenotypes. The augmentation in inhibitory synaptic transmission in the Nlgn3 KI mice is accompanied by a deficit in social interaction and, as observed in the Shank1 KO, enhanced spatial learning ability. These results are surprising because (1) a loss, rather than a gain of inhibition in different neural systems was hypothesized to contribute to ASDs (Hussman, 2001; Rubenstein & Merzenich, 2003), and (2) the individuals identified with mutations in Nlgn3 and -4 do not exhibit potentiated learning skills. The latter observations are consistent with a report of minimal aberrant behaviors in the Nlgn-3 KI mice (Chadman et al., 2008). Nevertheless, the results suggesting that a disequilibrium between excitatory and inhibitory synapses can affect social behavior (Sudhof, 2008) and that decreasing inhibitory transmission may be an effective therapy in some autism patients are worth pursuing. In fact, administration of the NMDA receptor partial co-agonist D-cycloserine can rescue the excessive grooming behavior in adult Nlgn1 KO mice (Blundell et al., 2010).
Unlike humans, the rodent Nlgn4 gene localizes to a still unknown autosome. Although there is only a 57% homology between the two species, the protein is found in synapses in both. Although Nlgn4 KO mice display abnormalities in two of the three core autistic symptoms, reciprocal social interaction, and impaired communication, as approximated by measuring USVs, they do not display repetitive behavior or impairments in some of the other autism symptoms such as sensory ability, sensorimotor gating, locomotion, exploratory activity, anxiety, or learning and memory (Jamain et al., 2008). These observations are consistent with those seen in patients with the NLGN4 mutation, who do not show these comorbid features. MRI analysis of the brains of Nlgn4 KO mice show a slight reduction in size of the total brain, cerebellum, and brain stem, and some of these neuroanatomical changes are reminiscent of autism.
To summarize, several Nlgn models exhibit strong construct validity with the rare human mutations associated with human ASDs. Moreover, the face validity of the Nlgn4 KO mice is fairly good at the behavioral level, but much remains to be done on its neuropathology.
One of the most validated susceptibility genes is contactin associated protein-like2 (CNTNAP2). This gene encodes a member of the neuronal neurexin superfamily that is involved in neuron-glial interactions and is very likely to be important in brain development (Abrahams et al., 2008b). An intriguing feature of CNTNAP2 is its enriched expression in circuits in the human cortex that are important for language development. Moreover, its expression is enriched in song nuclei important for vocal learning in the zebra finch, and feature is male-specific, as is the song behavior (Panaitof et al., 2010). In addition, (CNTNAP2) polymorphisms are associated with language disorders, and the expression of this gene can be regulated by FOXP2, a transcription factor that, when mutated, can cause language and speech disorders (Vernes et al., 2008). In light of these associations, it is important that recent study of the Cntnap2 KO mouse reveals a deficit in USVs. Moreover, these mice display the other core features of autism, repetitive behavior and a social interaction deficit. They also exhibit several other features of ASD: seizures, mild cortical laminar disorganization and hyperactivity (D. H. Geschwind, personal communication).
Engrailed homeobox 1 (EN1) and 2 encode transcription factors expressed during embryonic and postnatal stages that regulate the development of the cerebellum. EN2 localizes in proximity to an autism susceptibility locus on chromosome 7 (Liu et al., 2001; Alarcon et al., 2002), and genetic variations in EN2 have also been reported to associate with ASDs (Petit et al., 1995; Gharani et al., 2004; Benayed et al., 2005; Wang et al., 2008; Yang et al., 2008), although one report could not replicate such association (Zhong et al., 2003). Although mice homozygous for a mutation in En-1 lack a cerebellum and die shortly after birth (Wurst, Auerbach, & Joyner, 1994), En2 KO mice are viable and display some cerebellar pathologies resembling those reported in the brains of some autistic individuals, such as a decreased PC number, hypoplasia, and abnormal foliation (Kuemerle et al., 1997; Amaral, Schumann, & Nordahl, 2008). The juvenile KO mice display reduced social and play behaviors, and abnormal social behavior and repetitive self-grooming as adults (Cheh et al., 2006). In addition, although En2 KO mice display normal loco-motor activity in the open field, motor deficits are observed in specific tasks such as mid-air righting, hanging-wire grip strength, and rotorod. Learning and memory impairments are also evident in the water maze and modified open field with objects. At the neurochemical level, mutant mice exhibit increased cerebellar serotonin compared to controls but no alteration in dopamine levels in hippocampus, striatum, and frontal cortex or cerebellum. Thus, En2 KO mice display face validity for autism, except for the motor deficits, which can interfere with some behavioral tests. It will be of interest to examine USVs in this model.
Several lines of evidence indicate that changes in serotonin signaling may contribute to autism pathogenesis. Serotonin levels in platelets are elevated in autistic patients (Cook & Leventhal, 1996), and numerous polymorphisms in genes implicated in 5-HT signaling or metabolism have been reported in autism, including the serotonin-transporter gene SLC6A4 (SERT), monoamine oxidase A (MAOA), tryptophan 2,3 dioxygenase gene, and two serotonin receptors, 5-HT2A (HTR2A) and 5-HT7 (HTR7). Pharmacological modulation of the serotonin system using the 5-HT receptor antagonist risperidone improves ritualistic behavior and irritability of autistic children and, similarly, selective 5-HT reuptake inhibitors ameliorate repetitive thoughts and behaviors as well as mood disturbances. Conversely, depletion of tryptophan, a serotonin precursor, aggravates autistic symptoms (Hollander et al., 2005). Abnormalities in brain serotonin synthesis at different ages, as well as cortical asymmetries in serotonin synthesis, have been reported in children with autism (Chugani et al., 1997; Chugani et al., 1999). These alterations could be linked to abnormalities in cortical minicolumn organization in autism (Casanova & Tillquist, 2008). Serotonin signaling modulates various aspects of pre- and postnatal brain development (Gaspar, Cases, & Maroteaux, 2003), and some mouse lines with disruption in the 5-HT system show neuropathology consistent with those observed in autism. Behavioral changes observed in these mutants relate to mood, aggression, anxiety, depression, seizure, and learning and memory, all of which are relevant to autism.
A mouse line in which serotonin signaling is impaired is the Dhcr7 mutant. DHCR7 (7-dehydrocholesterol reductase) is an enzyme required for the biosynthesis of cholesterol, and mice lacking functional Dhcr7 display an increase in the area and intensity of serotonin immunoreactivity in the embryonic hindbrain (Waage-Baudet et al., 2003). Unfortunately, Dhcr7 KO mice die shortly after birth, precluding behavioral studies. In humans, DHCR7 deficiency causes the Smith–Lemli–Opitz syndrome (SLOS), a disease characterized by dysmorphic facial features, mental retardation, and limb defects (Yu & Patel, 2005). Approximately 50% of patients with SLOS are also diagnosed with autism (Tierney et al., 2001). Levels of cholesterol are decreased in some idiopathic autistic children (Tierney et al., 2006), and cholesterol dietary supplementation improves autistic-like behavior of patients with SLOS (Aneja & Tierney, 2008). Presently, the mechanisms by which cholesterol deficiency affects serotonin pathways are not fully elucidated, but it is known that cholesterol can modulate the functional activity of MAO (Caramona et al., 1996) and SERT (Scanlon, Williams, & Schloss, 2001). Investigation of Dhcr7 heterozygous mice or development of conditional mutants could further the understanding of the role of cholesterol in autism.
Bdnf-deficient mice also display alterations in the serotonin system. Signaling mediated by BDNF and its receptor tyrosine kinase (TrkB) is crucial for serotonergic neuronal development, as well as a wide variety of other neuronal functions. Variants in the BDNF gene have been associated with autism (Nishimura et al., 2007), and post mortem analysis of brains from autistic adults show enhanced levels of BDNF (Perry et al., 2001), whereas blood and serum levels in autism are controversial (cf. Croen et al., 2008). Various Bdnf or TrkB mutant mouse lines are available, including heterozygous null mice (homozygous KOs are not viable), conditional, and inducible Bdnf KO mice. Presence and severity of behavioral alterations in these mice depends on the stage at which BDNF is depleted, the brain regions targeted for BDNF deficiency, and the gender of the mutants (cf. Monteggia et al., 2004). Autistic-like behavioral impairments commonly reported are heightened aggression, hyperactivity, depression-like traits, and, in some instances, altered locomotor activity. Hyperphagia is reported in some Bdnf mutant lines, a finding inconsistent with autism per se but also observed in PWS. Despite behavioral deficits, surprisingly, dendritic morphology and GAD67 are not altered in brains from fetal and postnatal KOs (Hashimoto et al., 2005; Hill et al., 2005). In contrast, double Bdnf +/- x Sert -/- mutants display exacerbated anxiety in the elevated plus maze, greater elevation in plasma ACTH after stressful stimulus, and reduction in the size of dendrites of hippocampal and hypothalamic neurons in comparison to WT, Sert+/+ x Bdnf+/- and Sert-/-x Bdnf +/+ mice (Ren-Patterson et al., 2005). Because autism is often considered to be a multigenic disorder, investigation of gene/gene interaction is a logical approach.
Urokinase Plasminogen Activator Receptor Knockout Mice
Variations in the MET gene encoding a receptor tyrosine kinase are associated with autism (Campbell et al., 2006). Moreover, post mortem analysis of cortical tissue from autistic individuals reveals decreased levels of MET protein in comparison to matched controls (Campbell et al., 2007). Disruption in signaling mediated by MET and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), may be particularly relevant to the etiology of the disorder because, in addition to playing a key role in the CNS during development and adulthood, it is also involved in gastrointestinal repair and regulation of the immune system, two other systems that are altered in autism (Vargas et al., 2005). The PI3K/Akt pathway is one of the prominent signaling cascades activated by MET, which thereby antagonizes PTEN function. In the CNS, HGF/SF-MET signaling promotes the migration of cortical interneurons during development (Powell, Mars, & Levitt, 2001), contributes to cerebellar development and function (Leraci, Forni, & Ponzetto, 2002), stimulates dendritic growth in cortical neurons (Gutierrez et al., 2004), and induces protein clustering at excitatory synapses (Tyndall & Walikonis, 2006). Although genetic deletion of Met causes embryonic lethality, the KO of urokinase plasminogen activator receptor (uPar), which exhibits reduced uPA activity (the protease required for the activation of HGF), is viable and displays a diminution in HGF levels and, as observed in autism, in MET levels. The uPar KO mice display increased anxiety and are prone to seizures (Powell et al., 2003), features that are relevant to autism (Tuchman & Rapin, 2002). Whether these mice display deficits in any core symptoms of the disorder has not been reported. Gastrointestinal and immune pathology also needs to be assessed in these mutants.
Disrupted in Schizophrenia-1
A balanced translocation between chromosome 1 and 11 t (1;11) (q42.2;q14.1) cosegregates with schizophrenia and related disorders in a large Scottish family (St Clair et al., 1990; Blackwood et al., 2001). Disrupted in Schizophrenia-1 (DISC1) is altered by this translocation (Muir et al., 1995; Millar et al., 2000; Millar et al., 2001), and there is an association between variations within the DISC locus and autism and Asperger syndrome (Kilpinen et al., 2008). DISC1 is a scaffold protein, which, through interactions with various proteins (e.g., PDE4B, LIS1, NDEL1, NDE1, CIT, MAP1A), regulates cAMP signaling, cortical neuron migration, neurite outgrowth, glutamatergic neurotransmission, and synaptogenesis (Muir, Pickard, & Blackwood, 2008). There are a number of Disc1 mouse variants currently available: mice carrying a truncated version of the endogenous Disc1 ortholog, transgenic lines with inducible expression of mutant human DISC1 (hDISC1), and lines carrying N-ethyl-N-nitrosourea-induced mutations in Disc1 (Chubb et al., 2008). Hippocampal neurons in mice with mutations of endogenous Disc1 display dendritic misorientation and reduced number of spines, as observed in the Fmr1 KO mice. These mice display a working memory deficit but do not show deficits in PPI or latent inhibition (Koike et al., 2006; Kvajo et al., 2008). Transgenic mice expressing hDISC1 in forebrain regions show a mild enlargement of the lateral ventricles in comparison to WT animals, and neurite outgrowth is decreased in primary cortical neurons from these mutants. These neuropathologies are associated with altered social interaction and enhanced spontaneous locomotor activity in male hDISC1 mice and with mild impairment in spatial memory in females (Pletnikov et al., 2008). Tests assessing repetitive behavior and ultrasonic vocalizations remain to be reported. Further study of neuropathology in the various strains will also be important.
Oxytocin and Vasopressin
Neuropeptides and their associated receptors play a central role in the regulation of complex social behaviors. Several lines of evidence suggest that functional alterations in these systems may contribute not only to social deficits in autism but also to repetitive behaviors. (1) A reduction in oxytocin (OXT) plasma levels, associated with an elevation in the prohormone form, is observed in autistic children (Modahl et al., 1998; Green et al., 2001). Mixed results have been reported for OXT plasma levels in high-functioning adult autistic patients (Jansen et al., 2006; Andari et al., 2010). (2) Intranasal infusion of OXT reduces stereotyped behavior and improves eye contact, social memory and use of social information in high functioning autistic patients (Hollander et al., 2003, 2007; Guastella et al., 2009; Andari et al., 2010). (3) Genetic variations in OXT receptor and vasopressin receptor V1aR can be associated with autism (Donaldson & Young, 2008; Israel et al., 2008; Gregory et al., 2009). (4) Oxytocin receptor mRNA is decreased in post-mortem autism temporal cortex (Gregeory et al., 2009).
Current knowledge derived from studies in Oxt and Oxt receptor (Oxtr) KO mice underscore the subtle role of this system in aggression and anxiety. Thus, Oxt KO adult male progeny from homozygous crosses display high levels of aggression, whereas levels of aggression in Oxt KO adult male progeny from heterozygous crosses are either less pronounced or similar to WT mice, suggesting that absence of Oxt during prenatal stages modulates the development of aggression in adulthood (Ferguson et al., 2000; Winslow et al., 2000; Takayanagi et al., 2005). Oxt KO female mice also display exaggerated aggression under controlled stress conditions designed to mimic the natural environment, indicating a possible interaction between the postnatal environment and the Oxt system (Ragnauth et al., 2005). Similarly, Oxtr KO adult males display elevated aggressive behavior, as well as deficits in social discrimination (Takayanagi et al., 2005). Oxt KO adult mice nevertheless display reduced anxiety in the plus maze and acoustic startle reflex, a finding inconsistent with autism. In addition, as infants, both Oxt and Oxtr KO males emit fewer USVs in the isolation test than WT animals, which is also suggestive of decreased anxiety during maternal separation, but is also consistent with the lack of communication in ASD. The Oxt KO mice fail to recognize familiar conspecifics upon repeated social encounters, although olfactory and nonsocial memory are intact (Winslow & Insel, 2002). This has been interpreted as an autism-like social deficit, although social amnesia has not been described in autism. Comprehensive neuropathology remains to be reported in these strains. Given the implications for ASD in the human findings, further study of Oxt mutant mice is warranted, although striking species differences are apparent for Oxt and vasopressin, and their receptors (Insel, 2010).
Male V1aR KO mice exhibit deficits in olfactory social recognition and social interaction (Bielsky et al., 2004; Egashira et al., 2007). Similarly to Oxt and Oxtr KO mice, V1aR KO mice show reduced anxiety-like behavior in the elevated plus maze and the open field and the light/dark box, although high levels of anxiety are observed in the WT animals in comparison to other reports. No deficits in learning and memory in the Morris water maze or in PPI are detected, indicating that the face validity of this model is partial. V1bR KO adult females emit fewer USVs in a resident-intruder test. Although the number of USVs emitted by infant mutants is not affected during the conventional pup separation test, mutant pups fail to display maternal potentiation of USVs, which could suggest either a defect in a cognitive component or reduced anxiety (Scattoni et al., 2008). Although reduced anxiety is inconsistent with autism, V1bR antagonists could be tested to lower anxiety.
The BTBR mouse strain exhibits low levels of sociability at juvenile and adult ages, as well as abnormal social learning in the transmission of food preference test. Moreover, BTBR mice show a high level of spontaneous repetitive grooming, poor shift performance in a hole-board task, and a deficit in the water maze reversal task, which can be interpreted as the resistance to change in routine that is observed in autism (Bolivar, Walters, & Phoenix, 2007; Moy et al., 2007; Yang, Zhodzishsky, & Crawley, 2007; McFarlane et al., 2008; Moy et al., 2008). Finally, BTBR pups separated from their mother emit more and longer USVs in comparison to C57 pups (Scattoni et al., 2008). Their repertoire of vocalizations is also narrower in comparison to pups from standard mouse strains. The latter observation is significant, as human infants later diagnosed with autism make unusual vocalizations (Johnson, 2008). However, one might expect to see lower rates of USVs in pups if modeling the ASD communication deficit. Such a deficit is reported in adult BTBR mice (Wohr et al., 2010). Detailed study of the fine structure of USVs, as well as their behavioral functions in adult mice, is an important area for future studies of animal models of psychiatric disease.
A recent study indicates that BTBR mice display an exaggerated response to stress that is associated with high blood levels of corticosterone in comparison to C57 mice (Benno et al., 2009). Thus, it is not clear whether enhanced stress causes or aggravates the behavioral phenotype of these mice. Key anatomical features of BTBR mice are the absence of the corpus callosum and a reduced hippocampal commissure. These deficits correlate with impaired contextual fear memory, which could arise from an increased susceptibility to de-potentiation. Otherwise, electrophysiological properties of hippocampal slices from BTBR (LTP, paired pulse facilitation, and basal synaptic transmission) are similar to those of C57 (MacPherson et al., 2008). Thus, several BTBR behaviors are consistent with autism, and the most striking anatomical feature in this strain is consistent with many, but not all, studies of the corpus callosum in autism (Amaral, Schumann, & Nordahl, 2008).
A difficulty with this line is that comparisons are necessarily made to other, unrelated mouse lines, and it is not clear to which line (s) BTBR should be compared. For instance, similar to BTBR mice, but unlike C57 mice, BALB/c mice display low social behavior, reduced USVs and reduced empathy-like behavior (Silverman et al., 2010). Because it is likely that there is a wide variety of genetic differences between such strains, comparing their behaviors is not equivalent to comparing behaviors and neuropathology between mutant and WT mice of the same genetic background. Nonetheless, the search for the genes causing behavioral phenotypes is ongoing, and a single nucleotide polymorphism in Kmo, which encodes kynurenine 3-hydroxylase, has been found in BTBR mice when compared to unrelated strains (McFarlane et al., 2008). This enzyme regulates the synthesis of kynurenic acid, a neuroprotective compound for which levels are abnormal in other neuropsychiatric diseases, including schizophrenia.
Myocyte Enhancer Factor 2 KO mice
A recent homozygosity mapping study of autism loci identified several candidate genes that are regulated by myocyte enhancer factor 2 (MEF2) transcription factors (Morrow et al., 2008). MEF2 factors mediate synapse elimination. Conditional KO of Mef2c at the neural stem cell stage yields mice with fewer, smaller, and more compacted neurons that exhibit what is interpreted as immature electrophysiological network properties. It is of interest that these mice display marked paw-clasping stereotypy, possibly altered spatial memory, and complex changes in anxiety tests when tested as adults (Li et al., 2008). Indeed, such behaviors resemble those observed in Mecp2 mutants. In addition, a recent study revealed that active FMRP is required for MEF2-dependant synapse elimination, thus further pinpointing the molecular factors at play in regulating synapse number (Pfeiffer et al., 2010).
Copy Number Variations
Copy number variations (CNVs) are DNA fragments whose number is altered by deletion or duplication between various individuals. They are thought to account for a significant proportion of normal phenotypic variation within the human population (Freeman et al., 2006). Several recent studies have indicated that de novo CNVs associate with autism. Interestingly, some of the genes identified within the loci subject to CNVs in autism are related to synaptic or neuronal activity (e.g., SHANK3, NLGN4, and NRXN1) (for reviews, see Abrahams & Geschwind, 2008a; Cook & Scherer, 2008). Thus, genome-wide investigation of CNVs might further implicate or reveal novel candidate genes in autism, for which rodent mutant lines can be developed.
Autism is a common occurrence in children with brain lesions caused by hemorrhage or tumor (Asano et al., 2001; Limperopoulos et al., 2007). One example of this is TSC, a genetic disorder that causes benign lesions or tumors to form in many different organs, including the brain. MRI and positron emission tomography (PET) demonstrate correlations between abnormalities in the cortex and communication deficits, whereas changes in subcortical circuits correlate with stereotypies and lack of social interaction (Asano et al., 2001). Therefore, the study of autism in children with TSC and the development of animal lesion models may provide clues about autistic behavior.
Although brain lesions have commonly been used in animal models to study the circuitry underlying behaviors (Lavond & Steinmetz, 2003), interpretation of such results can be complex. First, the loss of a behavior does not prove that the lesioned brain area is the originating source for brain activity associated with that behavior. Second, lesions often damage axons passing through the brain area of interest, giving rise to erroneous conclusions about that brain region’s importance in the behavior. Third, behavioral testing is necessarily performed on subjects responding to injury with various inflammatory and regenerative mechanisms whose influence on behavior is poorly understood. More recent advances in the ability to silence particular neuronal populations using genetic techniques promise much greater sophistication in unraveling the circuitry underlying behavior.
The amygdala has reciprocal connections with many areas, including the orbital and medial prefrontal cortex and the hippocampus, which are implicated in autism. Several post mortem studies have demonstrated amygdala abnormalities in autistic subjects, such as altered developmental trajectory and fewer neurons (Amaral et al., 2008). In case reports, children with severe temporal lobe damage resulting from viral encephalitis, tumors, or other factors developed autistic symptoms (Sweeten et al., 2002). In children with TSC, symptoms of autism are strongly related to the presence of tubers in the temporal lobe (Gillberg et al., 1994). These findings, along with recent functional neuroimaging data, led Baron-Cohen to develop an “amygdala theory of autism” (2000), which suggests a crucial role for the amygdala in the impairment of social behavior. In addition, patients with amygdala lesions (Adolphs, 2003) and individuals with autism (Adolphs et al., 2001) appear to have similar deficits in recognizing complex emotions in facial expressions. Neonatal ibotenic acid lesion of the amygdala in the rat has been proposed as an animal model of neurodevelopmental disorders such as autism (Daenen et al., 2001; 2002a; 2002b; Diergaarde et al., 2004). In this model, animals display increased latency to play with social partners, decreased duration of contact, and hyperactivity as well as decreased adaptation and habituation to the open field, which is interpreted as locomotor stereotypy and low anxiety (Daenen et al., 2001; 2002a). Thus, excitotoxic lesions of the amygdala in the neonatal rat produce multiple behavioral abnormalities relevant to autism. This conclusion differs from that found in similar nonhuman primate studies (Amaral et al., 2003). Moreover, humans with amygdala lesions do not display deficits in social interaction like those seen in autism (Amaral et al., 2003).
Limbic system dysfunction is fundamental to autism (Amaral et al., 2008). Neonatal ibotenic acid lesion of the hippocampus in the rat causes locomotor stereotypy in the open field test, but there are mixed results concerning deficits in social behavior early in life or in adulthood (Daenen et al., 2002b; Silva-Gomez et al., 2003) In rodent models, hippocampal lesions grossly impair memory, and autistic subjects display a selective deficit in hippocampal-dependent memory (Lathe, 2006). Because there are only a few studies analyzing social behavior in hippocampus-lesioned rats, and the damage in this area has no, or only a temporary, effect in monkeys (Amaral et al., 2003), more research is required in this area.
Patients who suffer damage to the prefrontal cortex have problems in making decisions and in behaving appropriately in social situations where empathy and social and moral reasoning are appropriate (Anderson et al., 1999; Koenigs et al., 2007). There is also evidence that both the medial temporal lobe and dorsolateral prefrontal cortex are implicated in autism (Amaral et al., 2008). Moreover, lesions to the orbital and medial prefrontal cortex in nonhuman primates cause abnormal social personality expression, decision making, and loss of position within the social group (Butter & Snyder, 1972). Lesioning prefrontal cortex also provokes a decrease in positive social behaviors (grooming, huddling, and near-body contact) and socially communicative facial, vocal, and postural behaviors, as well as an increase in inappropriate social interactions (Myers et al., 1973). Consistent with these results are ibotenic acid lesion studies of the medial prefrontal cortex in rats (Schneider & Koch, 2005). In addition, the lesion-induced disturbances of juvenile play behavior in rodents may also contribute to the social deficits observed in adult animals, because play-fighting is important for the development of communicative skills and appropriate behavioral patterns. Further work on the rodent model showed that neonatal lesion of the medial prefrontal cortex leads to reduced anxiety in the elevated plus maze, increased motor activity in open field, and, more interestingly, perseverative behavior in a reward-related test of operant behavior (Schwabe et al., 2006). This is in line with the behavioral changes reported for cerebellum lesion models.
The cerebellum is involved not only in the regulation of motor skills but also in higher functions, including cognition, language, and emotional expression (Turner et al., 2007). Adults and children with cerebellar lesions have high social isolation, communicative disturbance, and deficits in cognitive processing (Eluvathingal et al., 2006; Limperopoulos et al., 2007). A common finding in autism is a loss of PCs (72% of cases; Palmen et al., 2004; 79% of cases; Amaral et al., 2008). Therefore, surgical or toxin lesions of the cerebellum are of particular interest in studying animal models of autism. In addition to cognitive dysfunction reported in a rat model of cerebellum lesion (Gaytan-Tocaven & Olvera-Cortes, 2004), there are two rat models displaying perseverative behavior, which is common in autism and is expressed as insistence on sameness as well as inability to understand and cope with novel situations. This kind of behavior is found in a rat model of early (P10) midline cerebellar lesion (Bobee et al., 2000). In addition, these animals display elevated spontaneous motor activity and exhibit lack of attention to environmental distractors. Unlike the autism phenotype, however, the lesioned animals are neophilic and less anxious than controls. Vermis-lesioned rats show a decreased coefficient of learning during extended training of an instrumental task, which is interpreted as perseverative behavior (Callu et al., 2007).
In sum, the lesion models support dysfunction in autism in several areas: the prefrontal cortex, the temporal lobe and the cerebellum. This may be because an early defect in the functioning of these areas of the brain alters the development of multiple other areas, however. Behavioral analysis has focused primarily on motor tasks and anxiety. These lesion models display hyperactivity and low anxiety in the open field, which is unlike the autism phenotype (Lathe, 2006). No changes, or decreased general social activity, are reported for rodent models with lesions in the amygdala, prefrontal cortex, or hippocampus. Early damage to the amygdala or the prefrontal cortex results in altered juvenile play behavior, the earliest form of non-mother-directed social behavior in rodents. Thus far, these lesion models display two types of behaviors impaired in autism—namely, a deficit in social behavior and stereotypy. It will be important to assay other types of social and communicative behavior (for example, ultrasonic vocalizations in different social contexts), as well as to compare the changes in brain pathology, biochemistry, and gene expression to those seen in autism.
Given that the background genotypes of the rat and mouse strains that are used for experiments are somewhat arbitrary, and that genotype is very important in autism, it is remarkable that both behaviors and neuropathology consistent with autism can be reproduced in rodents. This issue of background genotype could potentially become increasingly important as more sophisticated models incorporating human genetic variants are introduced. Although no single rodent model has yet been thoroughly studied at all levels of investigation, several models have already been explored in some depth. Among those that display face and construct validity are the maternal valproate and maternal infection models of environmental risk factors, as well as the NLGN-4, Frmr1, CNTNAP2, and MeCP2 models of genetic risk factors. Nonetheless, no model has been thoroughly investigated with all available experimental tools, including behavior, histology, biochemistry, electrophysiology, and imaging.
Challenges and Future Directions
• The fine structure of ultrasonic vocalizations, as well as their behavioral functions in adult mice, are intriguing areas for future study of potential communication abnormalities.
• Theory of mind, the ability to intuit another’s thinking, is an important deficit in autism. An analogous test of empathy can be done in mice, where observing cage mates experience stressful experiences can alter the witness’ responses to later tests (Langford et al., 2006; Chen, Panksepp & Lahvis, 2009). This assay should be widely tested in the available environmental and genetic models.
• To reach their full potential in mimicking the human situation, models of candidate genes should carry the variant identified in the human studies, not just a KO of the gene.
• It is now possible to test the hypothesis that the full autism phenotype may emerge from environmental risk factors acting on susceptibility genotypes.
• Multi-electrode recording, functional imaging, and immediate early gene activation studies will be important for mapping patterns of functional activity in rodent models and comparing it to fMRI data from human subjects.
• Translational, preclinical studies in several mouse models have already stimulated small clinical trials in ASD-related disorders. Although this will likely accelerate in the near future, significant species differences will undoubtedly lead to failures along the way.
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Research related to autism from the authors’ laboratory was supported by a McKnight Foundation Neuroscience of Brain Disorder Award, the Stanley Medical Research Institute, the National Institute of Mental Health, and the Binational Science, International Rett Syndrome, Cure Autism Now, Simons and Autism Speaks Foundations.
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