Mouse Model Of Autism Spectrum Disorder Research Articles

Photobiomodulation Attenuated Cognitive Dysfunction and Neuroinflammation in a Prenatal Valproic Acid-Induced Autism Spectrum Disorder Mouse Model.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication and interaction disorders, as well as repetitive and restrictive behaviors. To date, no effective treatment strategies have been identified. However, photobiomodulation (PBM) is emerging as a promising treatment for neurological and neuropsychiatric disorders. We used mice exposed to valproic acid (VPA) as a model of ASD and found that pathological behavioral and histological changes that may have been induced by VPA were attenuated by PBM treatment. Pregnant mice that had been exposed to VPA were treated with PBM three times. Thereafter, we evaluated the offspring for developmental disorders, motor function, hyperactivity, repetitive behaviors, and cognitive impairment. PBM attenuated many of the pathological behaviors observed in the VPA-induced ASD mouse model. In addition, pathophysiological analyses confirmed that the increase in activated microglia and astrocytes observed in the VPA-induced ASD mouse model was attenuated by PBM treatment. This suggests that PBM can counteract the behavioral changes caused by neuroinflammation in ASD. Therefore, our data show that PBM has therapeutic potential and may reduce the prevalence of neurodevelopmental disorders such as ASD.

Lactiplantibacillus plantarum ST-III-fermented milk improves autistic-like behaviors in valproic acid-induced autism spectrum disorder mice by altering gut microbiota.

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a rising incidence. More and more studies have shown that abnormal microbiota composition may aggravate the behavioral symptoms and biological signs of ASD, and interventions of probiotics and diet have emerged as a potential improvement measure. Lactiplantibacillus plantarum ST-III-fermented milk was applied as an oral intervention in a valproic acid (VPA)-induced ASD mice model, and the effect of probiotic intake on autistic-related behaviors and gut microbiota composition was evaluated by behavioral tests and 16S rRNA gene sequencing. Gender specificity was shown in VPA-induced behavioral abnormalities in a mouse model, and L. plantarum ST-III-fermented milk was effective in ameliorating the impaired social interaction in male ASD mouse models, but not for the anxiety behavior exhibited by female ASD mouse models. Meanwhile, dietary changes were found to be the main cause of the altered gut microbiota in mice, and additional intake of L. plantarum ST-III-fermented milk seemed to improve autistic-like behaviors in male ASD mouse models by modulating specific gut microbes. These findings suggest that L. plantarum ST-III-fermented milk may play a beneficial role in improving the behavioral symptoms of ASD and is expected to be one of the candidate functional foods for ASD.

Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders.

The development of autism spectrum disorders (ASDs) involves both environmental factors such as maternal diabetes and genetic factors such as neuroligins (NLGNs). NLGN2 and NLGN3 are two members of NLGNs with distinct distributions and functions in synapse development and plasticity. The relationship between maternal diabetes and NLGNs, and the distinct working mechanisms of different NLGNs currently remain unclear. Here, we first analyzed the expression levels of NLGN2 and NLGN3 in a streptozotocin-induced ASD mouse model and different brain regions to reveal their differences and similarities. Then, cryogenic electron microscopy (cryo-EM) structures of human NLGN2 and NLGN3 were determined. The overall structures are similar to their homologs in previous reports. However, structural comparisons revealed the relative rotations of two protomers in the homodimers of NLGN2 and NLGN3. Taken together with the previously reported NLGN2-MDGA1 complex, we speculate that the distinct assembly adopted by NLGN2 and NLGN3 may affect their interactions with MDGAs. Our results provide structural insights into the potential distinct mechanisms of NLGN2 and NLGN3 implicated in the development of ASD.

Why not try to predict autism spectrum disorder with crucial biomarkers in cuproptosis signaling pathway?

The exact pathogenesis of autism spectrum disorder (ASD) is still unclear, yet some potential mechanisms may not have been evaluated before. Cuproptosis is a novel form of regulated cell death reported this year, and no study has reported the relationship between ASD and cuproptosis. This study aimed to identify ASD in suspected patients early using machine learning models based on biomarkers of the cuproptosis pathway. We collected gene expression profiles from brain samples from ASD model mice and blood samples from humans with ASD, selected crucial genes in the cuproptosis signaling pathway, and then analysed these genes with different machine learning models. The accuracy, sensitivity, specificity, and areas under the receiver operating characteristic curves of the machine learning models were estimated in the training, internal validation, and external validation cohorts. Differences between models were determined with Bonferroni's test. The results of screening with the Boruta algorithm showed that FDX1, DLAT, LIAS, and ATP7B were crucial genes in the cuproptosis signaling pathway for ASD. All selected genes and corresponding proteins were also expressed in the human brain. The k-nearest neighbor, support vector machine and random forest models could identify approximately 72% of patients with ASD. The artificial neural network (ANN) model was the most suitable for the present data because the accuracy, sensitivity, and specificity were 0.90, 1.00, and 0.80, respectively, in the external validation cohort. Thus, we first report the prediction of ASD in suspected patients with machine learning methods based on crucial biomarkers in the cuproptosis signaling pathway, and these findings may contribute to investigations of the potential pathogenesis and early identification of ASD.

Genetic and environmental mouse models of autism reproduce the spectrum of the disease.

Genetic and environmental factors increase autism spectrum disorder (ASD) incidence, and this has led to the generation of corresponding animal models, with some showing strong construct and face validity. This short review focuses on results we have recently obtained with environmental and genetic mouse models of ASD and that are the valproic acid, the poly I:C and the Shank 3 models. This has allowed us to provide a comparative description of these widely used animal models providing an interesting perspective as to the pros and cons of each one of them, in our experimental settings. In these papers, we focused on motor and gait disorders which are currently not included in the diagnosis criteria, but which may provide new insights to ASD pathophysiology potentially leading to innovative therapies for a disease that currently has none. In all these models, we reported behavioral, cellular and molecular alterations related to the cerebellum. Motor and gait deficits were observed to various degrees in animal models and, when strongly present, they were correlated to the severity of social deficits as well as to the number of cerebellar Purkinje cells. Additionally, we also reported that, like in humans, males are more severely affected than females in these ASD models. These findings, along with an increasing body of literature, open new hopes in the ASD field pointing to brain regions, such the cerebellum, that are at the crossroads between cognitive, social and motor deficits. Targeting these brain regions and their underlying pathways and synaptic connections may prove of significant benefits.

Long-term behavioral effects of prenatal stress in the Fmr1-knock-out mouse model for fragile X syndrome.

Fragile X syndrome (FXS) is a major neurodevelopmental disorder and the most common monogenic cause of autism spectrum disorder (ASD). FXS is caused by a mutation in the X-linked FMR1 gene leading to the absence of the FMRP protein, inducing several behavioral deficits, including motor, emotional, cognitive, and social abnormalities. Beside its clear genetic origins, FXS can be modulated by environmental factors, e.g., stress exposure: indeed the behavioral phenotype of FXS, as well as of ASD patients can be exacerbated by the repeated experience of stressful events, especially early in life. Here we investigated the long-term effects of prenatal exposure to unpredictable chronic stress on the behavioral phenotype of the Fmr1-knock-out (KO) mouse model for FXS and ASD. Mice were tested for FXS- and ASD-relevant behaviors first at adulthood (3 months) and then at aging (18 months), in order to assess the persistence and the potential time-related progression of the stress effects. Stress induced the selective emergence of behavioral deficits in Fmr1-KO mice that were evident in spatial memory only at aging. Stress also exerted several age-specific behavioral effects in mice of both genotypes: at adulthood it enhanced anxiety levels and reduced social interaction, while at aging it enhanced locomotor activity and reduced the complexity of ultrasonic calls. Our findings underline the relevance of gene-environment interactions in mouse models of neurodevelopmental syndromes and highlight the long-term behavioral impact of prenatal stress in laboratory mice.

Maternal treatment with sodium butyrate reduces the development of autism-like traits in mice offspring

Several studies indicate a relationship between maternal gut microbiota alteration and increased risk of autism spectrum disorders (ASD) in offspring. The possibility of compensating for such metabolic dysfunction at a very early stage of disease via maternal treatment has not been enough explored. Here, we examined in BTBR mouse model of ASD the effect of maternal treatment with the gut microbial metabolite butyrate (BUT) on the behavioral and synaptic plasticity deficits in juvenile and adult offspring. We show that BUT treatment of BTBR dams rescues the social and partially the repetitive behavior deficits in the offspring. In addition, maternal BUT implementation prevents the cerebellar cortex hypertrophy as well as the Purkinje cells firing and long-term synaptic plasticity deficits in BTBR mice. Our results demonstrate, for the first time, that maternal BUT treatment can improve ASD-like symptoms in offspring thus providing new directions for the early treatment of neurodevelopmental disorders.

Autoantibody profiling of monoamine oxidase A knockout mice, an autism spectrum disorder model

Monoamine oxidase A (MAO A) is the critical enzyme to degrade serotonin in the brain and the knockout mouse exhibits hyperserotonemia and abnormalities that are observed in autism spectrum disorder (ASD). Thus, the MAO A knockout mouse is a valuable model for studying neurological and behavioral impairments in ASD. Based on the immune dysfunction hypothesis, dysregulated humoral immunity may cause neurological impairments. To address this hypothesis, we use high-density proteome microarray to profile the serum antibodies in both wild-type and MAO A knockout mice. The distingue autoantibody signatures were observed in the MAO A knockout and wild-type controls and showed 165 up-regulated and 232 down-regulated autoantibodies. The up-regulated autoantibodies were prone to target brain tissues while down-regulated ones were enriched in sex organs. The identified autoantibodies help bridge the gap between ASD mouse models and humoral immunity, not only yielding insights into the pathological mechanisms but also providing potential biomarkers for translational research in ASD.

Transient hearing abnormalities precede social deficits in a mouse model of autism

Hearing abnormalities are important symptoms of autism spectrum disorders (ASDs), a neurological and developmental disorder. However, the characteristics of hearing abnormalities associated with ASD during development have not been fully investigated. We found that in Shank3B knockout mice (a high-confidence mouse model of ASD), transient hearing abnormalities can be found in auditory brainstem response, auditory cortical activity, as well as acoustic startle response. More importantly, all hearing abnormalities at 4 weeks were most prominent and preceded the onset of social deficits at 6 weeks. These hearing abnormalities gradually recovered with age. In addition, analysis of ABR data at 4 weeks using Support Vector Machine (SVM) can faithfully predict the genotype of mice with an accuracy of 85.71%. These findings not only revealed hearing changes in Shank3B knockout autistic-like mice during development, but also suggested that hearing abnormalities could potentially be used as an early and effective indicator of ASD risk.

Enhanced fear limits behavioral flexibility in Shank2-deficient mice

BackgroundA core symptom of autism spectrum disorder (ASD) is repetitive and restrictive patterns of behavior. Cognitive inflexibility has been proposed as a potential basis for these symptoms of ASD. More generally, behavioral inflexibility has been proposed to underlie repetitive and restrictive behavior in ASD. Here, we investigated whether and how behavioral flexibility is compromised in a widely used animal model of ASD.MethodsWe compared the behavioral performance of Shank2-knockout mice and wild-type littermates in reversal learning employing a probabilistic classical trace conditioning paradigm. A conditioned stimulus (odor) was paired with an unconditioned appetitive (water, 6 µl) or aversive (air puff) stimulus in a probabilistic manner. We also compared air puff-induced eye closure responses of Shank2-knockout and wild-type mice.ResultsMale, but not female, Shank2-knockout mice showed impaired reversal learning when the expected outcomes consisted of a water reward and a strong air puff. Moreover, male, but not female, Shank2-knockout mice showed stronger anticipatory eye closure responses to the air puff compared to wild-type littermates, raising the possibility that the impairment might reflect enhanced fear. In support of this contention, male Shank2-knockout mice showed intact reversal learning when the strong air puff was replaced with a mild air puff and when the expected outcomes consisted of only rewards.LimitationsWe examined behavioral flexibility in one behavioral task (reversal learning in a probabilistic classical trace conditioning paradigm) using one ASD mouse model (Shank2-knockout mice). Thus, future work is needed to clarify the extent to which our findings (that enhanced fear limits behavioral flexibility in ASD) can explain the behavioral inflexibility associated with ASD. Also, we examined only the relationship between fear and behavioral flexibility, leaving open the question of whether abnormalities in processes other than fear contribute to behavioral inflexibility in ASD. Finally, the neurobiological mechanisms linking Shank2-knockout and enhanced fear remain to be elucidated.ConclusionsOur results indicate that enhanced fear suppresses reversal learning in the presence of an intact capability to learn cue-outcome contingency changes in Shank2-knockout mice. Our findings suggest that behavioral flexibility might be seriously limited by abnormal emotional responses in ASD.

Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism.

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (Mef2c-Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c-Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types; and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments.SIGNIFICANCE STATEMENT This is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.

Does the stranger mouse strain matter to female BTBR mice?

Autism spectrum disorder (ASD) is characterized by deficits in social communication and repetitive behaviors/restricted interests. One mouse model of ASD is the BTBR T+Itprtf/J (BTBR) mice which display low levels of social behavior in several tests. The social approach test is used to examine the preference for social interaction between a stranger mouse or a novel object. While female BTBR mice have been used in the social approach test, no one has examined the degree to which the strain of the stranger mouse will affect social behavior. The current experiment tested female BTBR subject mice in the social approach test with stranger mice from different strains including the BTBR, 129S1/SvImJ (129), and C57BL/6J (B6) mice, of which the B6 mice are most social. The results show that female BTBR mice overall spent significantly more time in the stranger mouse chamber. However, further analysis revealed that the subject mice spent significantly more time in the stranger mouse chamber when the stranger was from the B6 strain, but not the BTBR or 129 strains. The BTBR female mice also sniffed the B6 and 129 stranger mice more than the novel object. This suggests that BTBR females are more social with mice that display high levels of social behavior, but less so with less social mice.

Hyperbaric Oxygen Therapy Alleviates Social Behavior Dysfunction and Neuroinflammation in a Mouse Model for Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder (NDD) characterized by impaired social communication and repetitive behavior, among other symptoms. ASD is highly heritable, with SHANK3 being one of the high-risk genes for ASD. In recent years, knowledge has been growing regarding the neuroplasticity effect induced by hyperbaric oxygen therapy (HBOT) and its potential use for ASD. Here, we characterized the effect of HBOT on a mouse model for ASD with the human genetic condition of InsG3680 mutation in the Shank3 gene. As compared to placebo, HBOT improved social behavior and reduced neuroinflammation in the cortex of the InsG3680(+/+) mice. Specifically, HBOT induced upregulation of Insulin-like growth factor 1 (Igf1) expression levels and reduced the number of Iba1-positive cells in the mouse model for ASD compared to placebo control. Together, our research suggests that HBOT has the potential to improve the clinical outcome of ASD by ameliorating some of the core pathophysiological processes responsible for the development of the disorder.

Lactobacillus plantarum ST-III modulates abnormal behavior and gut microbiota in a mouse model of autism spectrum disorder

Probiotic treatment might improve autism spectrum disorder (ASD) behavior. In this study, we investigated the improvement effects of Lactobacillus plantarum ST-III on a mouse model of ASD, which was constructed using triclosan. After two weeks of L. plantarum ST-III oral feeding, autism-like social deficits in male mouse models were ameliorated. L. plantarum ST-III also attenuated the self-grooming and freezing times of female mice. High-throughput sequencing revealed changes in the gut microbiota after L. plantarum ST-III intervention. In the female probiotic group, the abundance of beneficial Lachnospiraceae bacteria increased, whereas that of harmful Alistipes bacteria decreased. Correlation analysis showed that amelioration of abnormal behavior in a mouse model of ASD was related to the involvement of certain metabolic pathways. A reduction in the abundance of Alistipes was involved in stereotyped behavioral improvement. Thus, oral supplementation with L. plantarum ST-III can help improve social behavior in a male mouse model of ASD and contribute to more balanced intestinal homeostasis.

Shank3 influences mammalian sleep development.

Sleep problems are prevalent in autism spectrum disorder (ASD), can be observed before diagnosis, and are associated with increased restricted and repetitive behaviors. Therefore, sleep abnormalities may be a core feature of the disorder, but the developmental trajectory remains unknown. Animal models provide a unique opportunity to understand sleep ontogenesis in ASD. Previously we showed that adult mice with a truncation in the high-confidence ASD gene Shank3 (Shank3∆C ) recapitulate the clinical sleep phenotype. In this study we used longitudinal electro-encephalographic (EEG) recordings to define, for the first time, changes in sleep from weaning to young adulthood in an ASD mouse model. We show that Shank3∆C male mice sleep less overall throughout their lifespan, have increased rapid eye movement (REM) sleep early in life despite significantly reduced non-rapid eye movement (NREM) sleep, and have abnormal responses to increased sleep pressure that emerge during a specific developmental period. We demonstrate that the ability to fall asleep quickly in response to sleep loss develops normally between 24 and 30 days in mice. However, mutants are unable to reduce sleep latency after periods of prolonged waking and maintain the same response to sleep loss regardless of age. This phenomenon seems independent of homeostatic NREM sleep slow-wave dynamics. Overall, our study recapitulates both preclinical models and clinical studies showing that reduced sleep is consistently associated with ASD and suggests that problems falling asleep may reflect abnormal development of sleep and arousal mechanisms.

Amygdala neural ensemble mediates mouse social investigation behaviors.

Innate social investigation behaviors are critical for animal survival and are regulated by both neural circuits and neuroendocrine factors. Our understanding of how neuropeptides regulate social interest, however, is incomplete at the current stage. In this study, we identified the expression of secretin (SCT) in a subpopulation of excitatory neurons in the basolateral amygdala. With distinct molecular and physiological features, BLASCT+ cells projected to the medial prefrontal cortex and were necessary and sufficient for promoting social investigation behaviors, whilst other basolateral amygdala neurons were anxiogenic and antagonized social behaviors. Moreover, the exogenous application of secretin effectively promoted social interest in both healthy and autism spectrum disorder model mice. These results collectively demonstrate a previously unrecognized group of amygdala neurons for mediating social behaviors and suggest promising strategies for social deficits.

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

BackgroundPatients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3WT/ΔC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption.MethodsWe recorded sleep behavior in developing Shank3ΔC/ΔC, Shank3WT/ΔC, and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3WT/ΔC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults.ResultsMale and female Shank3ΔC/ΔC mice slept significantly less than wild-type and Shank3WT/ΔC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3WT/ΔC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3WT/ΔC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3WT/ΔC subjects had a significant reduction in risk aversion. CON Shank3WT/ΔC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests.LimitationsThis study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities.ConclusionOur study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

Attenuation of Autism-like Behaviors by an Anthocyanin-Rich Extract from Portuguese Blueberries via Microbiota-Gut-Brain Axis Modulation in a Valproic Acid Mouse Model.

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental pathologies whose current treatment is neither curative nor effective. Anthocyanins are naturally occurring compounds abundant in blueberries and in other red fruits which have been shown to be successful in the treatment of several neurological diseases, at least in in vitro and in vivo disease models. The aim of the present work was to study the ability of an anthocyanin-rich extract (ARE) obtained from Portuguese blueberries to alleviate autism-like symptoms in a valproic acid (VPA) mouse model of ASD and to get insights into the underlying molecular mechanisms of such benefits. Therefore, pregnant BALB/c females were treated subcutaneously with a single dose of VPA (500 mg/kg) or saline on gestational day 12.5. Male offspring mice were orally treated with the ARE from Portuguese blueberries (30 mg/kg/day) or the vehicle for three weeks, and further subjected to behavioral tests and biochemical analysis. Our data suggested that the ARE treatment alleviated autism-like behaviors in in utero VPA-exposed mice and, at the same time, decreased both neuroinflammation and gut inflammation, modulated the gut microbiota composition, increased serotonin levels in cerebral prefrontal cortex and gut, and reduced the synaptic dysfunction verified in autistic mice. Overall, our work suggests that anthocyanins extracted from Portuguese blueberries could constitute an effective strategy to ameliorate typical autistic behaviors through modulation of the microbiota–gut–brain axis.

Transcriptomic analysis in the striatum reveals the involvement of Nurr1 in the social behavior of prenatally valproic acid-exposed male mice

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that exhibits neurobehavioral deficits characterized by abnormalities in social interactions, deficits in communication as well as restricted interests, and repetitive behaviors. The basal ganglia is one of the brain regions implicated as dysfunctional in ASD. In particular, the defects in corticostriatal function have been reported to be involved in the pathogenesis of ASD. Surface deformation of the striatum in the brains of patients with ASD and their correlation with behavioral symptoms was reported in magnetic resonance imaging (MRI) studies. We demonstrated that prenatal valproic acid (VPA) exposure induced synaptic and molecular changes and decreased neuronal activity in the striatum. Using RNA sequencing (RNA-Seq), we analyzed transcriptome alterations in striatal tissues from 10-week-old prenatally VPA-exposed BALB/c male mice. Among the upregulated genes, Nurr1 was significantly upregulated in striatal tissues from prenatally VPA-exposed mice. Viral knockdown of Nurr1 by shRNA significantly rescued the reduction in dendritic spine density and the number of mature dendritic spines in the striatum and markedly improved social deficits in prenatally VPA-exposed mice. In addition, treatment with amodiaquine, which is a known ligand for Nurr1, mimicked the social deficits and synaptic abnormalities in saline-exposed mice as observed in prenatally VPA-exposed mice. Furthermore, PatDp+/− mice, a commonly used ASD genetic mouse model, also showed increased levels of Nurr1 in the striatum. Taken together, these results suggest that the increase in Nurr1 expression in the striatum is a mechanism related to the changes in synaptic deficits and behavioral phenotypes of the VPA-induced ASD mouse model.

Autism Spectrum Disorder Model Mice Induced by Prenatal Exposure to Valproic Acid Exhibit Enhanced Empathy-Like Behavior via Oxytocinergic Signaling.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms, including impairments in social behavior and repetitive interests. Recent studies have revealed that individuals with ASD also display decreased empathy, ultimately leading to difficulties in social relationships; however, another report indicated that individuals with ASD have enhanced emotional empathy. Nonetheless, the neurobiological mechanisms underlying altered empathy in individuals with ASD remain unclear. In this study, we assessed empathy-like behaviors in valproic acid (VPA)-treated mice-a mouse model of ASD with observational fear learning. We then investigated the brain regions and signaling systems responsible for the altered empathy-like behaviors in VPA-treated mice. As a result, mice prenatally exposed to VPA displayed increased empathy-like behaviors, which were not attributed to altered sensitivity to auditory stimuli or enhanced memory for pain-related contexts. Immunohistochemical analysis revealed that the number of c-Fos positive oxytocinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) was significantly higher in VPA-treated mice after observational fear learning. Finally, we found that pretreatment with L-368899, an antagonist of the oxytocin receptor, repressed the empathetic behavior in VPA-treated mice. These results suggest that VPA-treated ASD model animals showed increased emotional empathy-like behaviors through the hyperactivation of PVN oxytocinergic neurons for the first time. Further investigation of this hyperactivity will help to identify extrinsic stimuli and the condition which are capable of activation of PVN oxytocinergic neurons and to identify novel approach to enhance oxytocin signaling, which ultimately pave the way to development of novel therapy for ASD.