Mouse Model Of Autism Spectrum Disorder Research Articles

Enhanced oligodendrocyte maturation and myelination in a mouse model of Timothy syndrome.

To study the role of L-type voltage-gated Ca++ channels in oligodendrocyte development, we used a mouse model of Timothy syndrome (TS) in which a gain-of-function mutation in the α1 subunit of the L-type Ca++ channel Cav1.2 gives rise to an autism spectrum disorder (ASD). Oligodendrocyte progenitor cells (OPCs) isolated from the cortex of TS mice showed greater L-type Ca++ influx and displayed characteristics suggestive of advanced maturation compared to control OPCs, including a more complex morphology and higher levels of myelin protein expression. Consistent with this, expression of Cav1.2 channels bearing the TS mutation in wild-type OPCs triggered process formation and promoted oligodendrocyte-neuron interaction via the activation of Ca++ /calmodulin-dependent protein kinase II. To ascertain whether accelerated OPC maturation correlated with functional enhancements, we examined myelination in the TS brain at different postnatal time points. The expression of myelin proteins was significantly higher in the corpus callosum, cortex and striatum of TS animals, and immunohistochemical analysis for oligodendrocyte stage-specific markers revealed an increase in the density of myelinating oligodendrocytes in several areas of the TS brain. Along the same line, electron microscopy studies in the corpus callosum of TS animals showed significant increases both in the percentage of myelinated axons and in the thickness of myelin sheaths. In summary, these data indicate that OPC development and oligodendrocyte myelination is enhanced in the brain of TS mice, and suggest that this mouse model of a syndromic ASD is a useful tool to explore the role of L-type Ca++ channels in myelination.

Altered Amygdala Excitation and CB1 Receptor Modulation of Aggressive Behavior in the Neuroligin-3R451C Mouse Model of Autism.

Understanding neuronal mechanisms underlying aggression in patients with autism spectrum disorder (ASD) could lead to better treatments and prognosis. The Neuroligin-3 (NL3)R451C mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown. It is well established that NL3R451C mice have imbalanced excitatory and inhibitory synaptic activity in the hippocampus and somatosensory cortex. The amygdala plays a role in modulating aggressive behavior, however potential changes in synaptic activity in this region have not previously been assessed in this model. We investigated whether aggressive behavior is robustly present in mice expressing the R451C mutation, following back-crossing onto a congenic background strain. Endocannabinoids influence social interaction and aggressive behavior, therefore we also studied the effects of cannabinoid receptor 1 (CB1) agonist on NL3R451C mice. We report that NL3R451C mice have increased amplitude of miniature excitatory postsynaptic currents (EPSCs) with a concomitant decrease in the amplitude of inhibitory postsynaptic currents (IPSCs) in the basolateral amygdala. Importantly, we demonstrated that NL3R451C mice bred on a C57Bl/6 background strain exhibit an aggressive phenotype. Following non-sedating doses (0.3 and 1.0 mg/kg) of the CB1 receptor agonist WIN55,212-2 (WIN), we observed a significant reduction in aggressive behavior in NL3R451C mice. These findings demonstrate altered synaptic activity in the basolateral amygdala and suggest that the NL3R451C mouse model is a useful preclinical tool to understand the role of CB1 receptor function in aggressive behavior.

Dysregulation of Parvalbumin Expression in the Cntnap2-/- Mouse Model of Autism Spectrum Disorder.

Due to the complex and heterogeneous etiology of autism spectrum disorder (ASD), identification of convergent pathways and/or common molecular endpoints in the pathophysiological processes of ASD development are highly needed in order to facilitate treatment approaches targeted at the core symptoms. We recently reported on decreased expression of the Ca2+-binding protein parvalbumin (PV) in three well-characterized ASD mouse models, Shank1−/−, Shank3B−/− and in utero VPA-exposed mice. Moreover, PV-deficient mice (PV+/− and PV−/−) were found to show behavioral impairments and neuroanatomical changes closely resembling those frequently found in human ASD individuals. Here, we combined a stereology-based approach with molecular biology methods to assess changes in the subpopulation of PV-expressing (Pvalb) interneurons in the recently characterized contactin-associated protein-like 2 (Cntnap2−/−) knockout mouse model of ASD. The CNTNAP2 gene codes for a synaptic cell adhesion molecule involved in neurodevelopmental processes; mutations affecting the human CNTNAP2 locus are associated with human ASD core symptoms, in particular speech and language problems. We demonstrate that in Cntnap2−/− mice, no loss of Pvalb neurons is evident in ASD-associated brain regions including the striatum, somatosensory cortex (SSC) and medial prefrontal cortex (mPFC), shown by the unaltered number of Pvalb neurons ensheathed by VVA-positive perineuronal nets. However, the number of PV-immunoreactive (PV+) neurons and also PV protein levels were decreased in the striatum of Cntnap2−/− mice indicating that PV expression levels in some striatal Pvalb neurons dropped below the detection limit, yet without a loss of Pvalb neurons. No changes in PV+ neuron numbers were detected in the cortical regions investigated and also cortical PV expression levels were unaltered. Considering that Cntnap2 shows high expression levels in the striatum during human and mouse embryonic development and that the cortico-striato-thalamic circuitry is important for speech and language development, alterations in striatal PV expression and associated (homeostatic) adaptations are likely to play an important role in Cntnap2−/− mice and, assumingly, in human ASD patients with known Cntnap2 mutations.

Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso-proteome and affects key proteins involved in vesicle release and synaptic function.

Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO•)-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypothesis that Shank3 mutation would generate downstream effects on PTM of critical proteins that lead to modification of synaptic functions. SNO-proteins in two ASD-related brain regions, cortex and striatum of young and adult InsG3680(+/+) mice (a human mutation-based Shank3 mouse model), were identified by an innovative mass spectrometric method, SNOTRAP. We found changes of the SNO-proteome in the mutant compared to WT in both ages. Pathway analysis showed enrichment of processes affected in ASD. SNO-Calcineurin in mutant led to a significant increase of phosphorylated Synapsin1 and CREB, which affect synaptic vesicle mobilization and gene transcription, respectively. A significant increase of 3-nitrotyrosine was found in the cortical regions of the adult mutant, signaling both oxidative and nitrosative stress. Neuronal NO• Synthase (nNOS) was examined for levels and localization in neurons and no significant difference was found in WT vs. mutant. S-nitrosoglutathione concentrations were higher in mutant mice compared to WT. This is the first study on NO•-related molecular changes and SNO-signaling in the brain of an ASD mouse model that allows the characterization and identification of key proteins, cellular pathways, and neurobiological mechanisms that might be affected in ASD.

Role of Microtubule-Associated Protein in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication, along with repetitive and restrictive patterns of behaviors or interests. Normal brain development is crucial to behavior and cognition in adulthood. Abnormal brain development, such as synaptic and myelin dysfunction, is involved in the pathogenesis of ASD. Microtubules and microtubule-associated proteins (MAPs) are important in regulating the processes of brain development, including neuron production and synaptic formation, as well as myelination. Increasing evidence suggests that the level of MAPs are changed in autistic patients and mouse models of ASD. Here, we discuss the roles of MAPs.

Common Defects of Spine Dynamics and Circuit Function in Neurodevelopmental Disorders: A Systematic Review of Findings From in Vivo Optical Imaging of Mouse Models.

In vivo optical imaging is a powerful tool for revealing brain structure and function at both the circuit and cellular levels. Here, we provide a systematic review of findings obtained from in vivo imaging studies of mouse models of neurodevelopmental disorders, including the monogenic disorders fragile X syndrome, Rett syndrome, and Angelman syndrome, which are caused by genetic abnormalities of FMR1, MECP2, and UBE3A, as well as disorders caused by copy number variations (15q11-13 duplication and 22q11.2 deletion) and BTBR mice as an inbred strain model of autism spectrum disorder (ASD). Most studies visualize the structural and functional responsiveness of cerebral cortical neurons to sensory stimuli and the developmental and experience-dependent changes in these responses as a model of brain functions affected by these disorders. The optical imaging techniques include two-photon microscopy of fluorescently labeled dendritic spines or neurons loaded with fluorescent calcium indicators and macroscopic imaging of cortical activity using calcium indicators, voltage-sensitive dyes or intrinsic optical signals. Studies have revealed alterations in the density, stability, and turnover of dendritic spines, aberrant cortical sensory responses, impaired inhibitory function, and concomitant failure of circuit maturation as common causes for neurological deficits. Mechanistic hypotheses derived from in vivo imaging also provide new directions for therapeutic interventions. For instance, it was recently demonstrated that early postnatal administration of a selective serotonin reuptake inhibitor (SSRI) restores impaired cortical inhibitory function and ameliorates the aberrant social behaviors in a mouse model of ASD. We discuss the potential use of SSRIs for treating ASDs in light of these findings.

Alterations in neuronal cytoskeletal and astrocytic proteins content in the brain of the autistic-like mouse strain C58/J

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficient social interaction, impaired communication as well as repetitive behaviors. ASD subjects present connectivity and neuroplasticity disturbances associated with morphological alterations in axons, dendrites, and dendritic spines. Given that the neuronal cytoskeleton and astrocytes have an essential role in regulating several mechanisms of neural plasticity, the aim of this work was to study alterations in the content of neuronal cytoskeletal components actin and tubulin and their associated proteins, as well as astrocytic proteins GFAP and TSP-1 in the brain of a C58/J mouse model of ASD. We determined the expression and regulatory phosphorylation state of cytoskeletal components in the prefrontal cortex, hippocampus, and cerebellum of C58/J mice by means of Western blotting. Our results show that autistic-like mice present: 1) region-dependent altered expression and phosphorylation patterns of Tau isoforms, associated with anomalous microtubule depolymerization; 2) reduced MAP2 A content in prefrontal cortex; 3) region-dependent changes in cofilin expression and phosphorylation, associated with abnormal actin filament depolymerizing dynamics; 4) diminished synaptopodin levels in the hippocampus; and 5) reduced content of the astrocyte-secreted protein TSP-1 in the prefrontal cortex and hippocampus. Our work demonstrates changes in the expression and phosphorylation of cytoskeletal proteins as well as in TSP-1 in the brain of the autistic-like mice C58/J, shedding light in one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain and laying the foundation for future investigations in this topic.

Computational Analysis of Neonatal Mouse Ultrasonic Vocalization.

Neonatal vocalization is structurally altered in mouse models of autism spectrum disorder (ASD). Our published data showed that pup vocalization, under conditions of maternal separation, contains sequences whose alterations in a genetic mouse model of ASD impair social communication between pups and mothers. We describe details of a method which reveals the statistical structure of call sequences that are functionally critical for optimal maternal care. Entropy analysis determines the degree of non-random call sequencing. A Markov model determines the actual call sequences used by pups. Sparse partial least squares discriminant analysis (sPLS-DA) identifies call sequences that differentiate groups and reveals the degrees of individual variability in call sequences between groups. These three sets of analyses can be used to identify the otherwise hidden call structure that is altered in mouse models of developmental neuropsychiatric disorders, including not only autism but also schizophrenia. © 2018 by John Wiley & Sons, Inc.

Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress. The inhibition of neurite outgrowth and expression of synaptic factors are observed in ASD. Similarly, ER stress suppresses the neurite outgrowth and expression of synaptic factors. Additionally, hyperplasia of the brain is observed in patients with ASD. ER stress also enhances neuronal differentiation. Synaptic factors, such as cell adhesion molecule and shank, play important roles in the formation of neural circuits. Thus, ER stress is associated with the abnormalities of neuronal differentiation, neurite outgrowth, and synaptic protein expression. ER stress elevates the expression of the ubiquitin-protein ligase HRD1 for the degradation of unfolded proteins. HRD1 expression significantly increased in the middle frontal cortex in the postmortem of patients with ASD. Moreover, HRD1 silencing improved the abnormalities induced by ER stress. Because other ubiquitin ligases are related with neurite outgrowth, ER stress may be related to the pathogenesis of neuronal developmental diseases via abnormalities of neuronal differentiation or maturation.

Adult Fmr1 knockout mice present with deficiencies in hippocampal interleukin-6 and tumor necrosis factor-α expression.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a single genetic mutation in the FMR1 gene. Mutations in the FMR1 gene are the largest monogenic cause of autism spectrum disorder (ASD), and thus both disorders share many of the same cognitive and behavioral impairments. There is increasing evidence suggesting that dysregulated immune responses play a role in the pathophysiology of ASD; however, the association between FXS and altered immunity requires further investigation. This study examined whether Fmr1 knockout (KO) and wild-type mice on a FVB/NJ background strain had altered cytokine expression at baseline levels in the hippocampus. Results showed Fmr1 KO mice to have decreased proinflammatory cytokine hippocampal mRNA expression, specifically interleukin (IL)-6 and tumor necrosis factor-α, compared with wild-type mice. However, no differences were detected in the expression levels of IL-1β, MCP-1, interferon-γ, or IL-10. Despite the high comorbidity between FXS and ASD, these results suggest that the Fmr1 KO mouse does not mimic the increased proinflammatory cytokine expression commonly found in ASD mouse models and patients. Further investigation of the immune profile of the Fmr1 KO mouse is critical to understand whether this deficiency of cytokines in the hippocampus is indicative of a broader immunologic deficit associated with FXS.

Effects of cross-rearing with social peers on myelination in the medial prefrontal cortex of a mouse model with autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Recent studies have indicated that early rehabilitative intervention can alleviate the symptoms of individuals with ASD. However, it remains unknown whether rehabilitative intervention can restore brain structures such as myelin, which generally shows abnormalities in individuals with ASD. Therefore, in the present study, we used a mouse model of ASD (BTBR mice) that demonstrated asocial behaviors and hypomyelination in the medial prefrontal cortex (mPFC) to investigate whether interaction with social peers (C57BL/6J mice) has an effect on myelination. We found that housing with C57BL/6J mice after weaning through adulthood increased the myelin thickness in mPFC, but not in the motor cortex, of BTBR mice. There was no effect of cross-rearing with C57BL/6J mice on axon diameter in mPFC of BTBR mice. This finding suggests that early rehabilitative intervention may alleviate myelin abnormalities in mPFC as well as clinical symptoms in individuals with ASD.

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice.

Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI-inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.

Association Among Gut Microbes, Intestinal Physiology, and Autism

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by two core symptoms: social deficits and increase in stereotypic/repetitive behaviors. Along with the core symptoms of ASD, other comorbid conditions can be observed in certain populations of people with ASD, such as gastrointestinal (GI) complications and altered gut microbiome (Adams et al., 2011 ; Parracho et al., 2005). Homeostasis of the GI system is closely regulated by the gut microbiota. Therefore, whether the gut microbiota is a contributing factor for ASD has been postulated recently. Several key questions have been raised. Do gut microbes contribute to the behavioral symptoms in ASD? How do gut microbes affect behavioral output through the gut–brain axis? How do gut and brain communicate with each other? Due to the complexity of the distal connection between gut and brain, these are the key questions that remain unanswered in the field.

The neurobiological bases of autism spectrum disorders: the R451C-neuroligin 3 mutation hampers the expression of long-term synaptic depression in the dorsal striatum.

Autism spectrum disorders (ASDs) comprise a heterogeneous group of disorders with a complex genetic etiology. Current theories on the pathogenesis of ASDs suggest that they might arise from an aberrant synaptic transmission affecting specific brain circuits and synapses. The striatum, which is part of the basal ganglia circuit, is one of the brain regions involved in ASDs. Mouse models of ASDs have provided evidence for an imbalance between excitatory and inhibitory neurotransmission. Here, we investigated the expression of long-term synaptic plasticity at corticostriatal glutamatergic synapses in the dorsal striatum of the R451C-NL3 phenotypic mouse model of autism. This mouse model carries the human R451C mutation in the neuroligin 3 (NL3) gene that has been associated with highly penetrant autism in a Swedish family. The R451C-NL3 mouse has been shown to exhibit autistic-like behaviors and alterations of synaptic transmission in different brain areas. However, excitatory glutamatergic transmission and its long-term plasticity have not been investigated in the dorsal striatum so far. Our results indicate that the expression of long-term synaptic depression (LTD) at corticostriatal glutamatergic synapses in the dorsal striatum is impaired by the R451C-NL3 mutation. A partial rescue of LTD was obtained by exogenous activation of cannabinoid CB1 receptors or enhancement of the endocannabinoid tone, suggesting that an altered cannabinoid drive might underlie the deficit of synaptic plasticity in the dorsal striatum of R451C-NL3 mice.

Depletion of Stercobilin in Fecal Matter from a Mouse Model of Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders lacking a clinical biomarker for diagnosis. Emerging evidence shows that intestinal microflora from ASD subjects can be distinguished from controls, suggesting metabolite differences due to the action of intestinal microbes may provide a means for identifying potential biomarkers for ASD. The aim of this study was to determine if quantitative differences in levels of stercobilin and stercobilinogen, metabolites produced by biological action of intestinal microflora, exist in the fecal matter between an ASD mouse model population and controls. Pairs of fecal samples were collected from two mouse groups, an ASD model group with Timothy syndrome 2 (TS2-NEO) and a gender-matched control group. After centrifugation, supernatant was spiked with an 18O-labeled stercobilin isotopomer and subjected to solid phase extraction for processing. Extracted samples were spotted on a stainless steel plate and subjected to matrix-assisted laser desorption and ionization mass spectrometry using dihydroxybenzoic acid as the matrix (n = 5). Peak areas for bilins and 18O-stercobilin isotopomers were determined in each fecal sample. A 40-45% depletion in stercobilin in TS2-NEO fecal samples compared with controls was observed with p < 0.05; a less dramatic depletion was observed for stercobilinogen. The results show that stercobilin depletion in feces is observed for an ASD mouse model vs. controls. This may help to explain recent observations of a less diverse microbiome in humans with ASD and may prove helpful in developing a clinical ASD biomarker.

P.3.e.006 - Influence of haloperidol and clozapine on apoptosis and autophagy in an animal model of schizophrenia

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Recent studies have indicated that early rehabilitative intervention can alleviate the symptoms of individuals with ASD. However, it remains unknown whether rehabilitative intervention can restore brain structures such as myelin, which generally shows abnormalities in individuals with ASD. Therefore, in the present study, we used a mouse model of ASD (BTBR mice) that demonstrated asocial behaviors and hypomyelination in the medial prefrontal cortex (mPFC) to investigate whether interaction with social peers (C57BL/6J mice) has an effect on myelination. We found that housing with C57BL/6J mice after weaning through adulthood increased the myelin thickness in mPFC, but not in the motor cortex, of BTBR mice. There was no effect of cross-rearing with C57BL/6J mice on axon diameter in mPFC of BTBR mice. This finding suggests that early rehabilitative intervention may alleviate myelin abnormalities in mPFC as well as clinical symptoms in individuals with ASD.

Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities.

Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of-function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy syndrome type 2 (TS2-neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2-neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced swim), serotonin neuron Fos activity in the caudal dorsal raphe, and serotonin type 1A receptor-dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain-of-function Cav1.2 mutation associated with Timothy syndrome has pleiotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L-type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions.

Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism

Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model.

Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut – namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.

Arid1b Haploinsufficiency Causes Abnormal Brain Gene Expression and Autism-Related Behaviors in Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that include poor social communication, restricted interests, and repetitive behaviors. Several ASD mouse models exhibit impaired social interaction, anxiety-like behavior, and elevated perseveration. Large-scale whole exome sequencing studies identified many genes putatively associated with ASD. Like chromodomain helicase DNA binding protein 8 (CHD8), the most frequently mutated gene in individuals with ASD, the candidate gene AT-rich interaction domain 1B (ARID1B) encodes a chromatin remodeling factor. Arid1b heterozygous knockout (hKO) mice exhibited ASD-like traits related to social behavior, anxiety, and perseveration, in addition to associated features reported in some cases of ASD, such as reduced weight, impaired motor coordination, and hydrocephalus. Hydrocephalus was present in 5 of 91 hKO mice, while it was not observed in wild-type littermates (0 of 188). Genome-wide gene expression patterns in Arid1b hKO mice were similar to those in ASD patients and Chd8-haploinsufficient mice, an ASD model, and to developmental changes in gene expression in fast-spiking cells in the mouse brain. Our results suggest that Arid1b haploinsufficiency causes ASD-like phenotypes in mice.