Model Of Autism Spectrum Disorder Research Articles

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder.

The hippocampus is one of the brain areas affected by autism spectrum disorder (ASD). Individuals with ASD typically have impairments in hippocampus-dependent learning, memory, language ability, emotional regulation, and cognitive map creation. However, the pathological changes in the hippocampus that result in these cognitive deficits in ASD are not yet fully understood. In the present review, we will first summarize the hippocampal involvement in individuals with ASD. We will then provide an overview of hippocampal structural and functional abnormalities in genetic, environment-induced, and idiopathic animal models of ASD. Finally, we will discuss some pharmacological and non-pharmacological interventions that show positive impacts on the structure and function of the hippocampus in animal models of ASD. A further comprehension of hippocampal aberrations in ASD might elucidate their influence on the manifestation of this developmental disorder and provide clues for forthcoming diagnostic and therapeutic innovation.

Amygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism.

Autism Spectrum Disorders (ASD) are principally diagnosed by three core behavioural symptoms, such as stereotyped repertoire, communication impairments and social dysfunctions. This complex pathology has been linked to abnormalities of corticostriatal and limbic circuits. Despite experimental efforts in elucidating the molecular mechanisms behind these abnormalities, a clear etiopathogenic hypothesis is still lacking. To this aim, preclinical studies can be really helpful to longitudinally study behavioural alterations resembling human symptoms and to investigate the underlying neurobiological correlates. In this regard, the BTBR T+ Itpr3tf/J (BTBR) mice are an inbred mouse strain that exhibits a pattern of behaviours well resembling human ASD-like behavioural features. In this study, the BTBR mice model was used to investigate neurochemical and biomolecular alterations, regarding Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), together with GABAergic, glutamatergic, cholinergic, dopaminergic and noradrenergic neurotransmissions and their metabolites in four different brain areas, i.e. prefrontal cortex, hippocampus, amygdala and hypothalamus. In our results, BTBR strain reported decreased noradrenaline, acetylcholine and GABA levels in prefrontal cortex, while hippocampal measurements showed reduced NGF and BDNF expression levels, together with GABA levels. Concerning hypothalamus, no differences were retrieved. As regarding amygdala, we found reduced dopamine levels, accompanied by increased dopamine metabolites in BTBR mice, together with decreased acetylcholine, NGF and GABA levels and enhanced glutamate content. Taken together, our data showed that the BTBR ASD model, beyond its face validity, is a useful tool to untangle neurotransmission alterations that could be underpinned to the heterogeneous ASD-like behaviours, highlighting the crucial role played by amygdala.

Development and Application of Technology for Neural Circuit Visualization - Secondary Publication.

The dynamics of neurite extension and synaptic connections are central issues in neural circuit research. The development of technologies for labeling purified cytoskeletal proteins with fluorescent dyes and introducing them into living neurons using microinjection greatly facilitated our understanding of cytoskeletal dynamics in neuronal axons. Imaging data showed that the cytoskeleton repeatedly polymerized and depolymerized within the axon, and elongation was driven by the new cytoskeleton formed at the axon tip. This finding significantly revised previously proposed models that explained slow axonal transport. After the discovery of green fluorescent protein (GFP), its potential application to the live imaging of neurons was recognized in the 1990s, and a new method for visualizing synapses using GFP-tagged postsynaptic scaffolding molecules was established. This method revealed the continuous turnover of synapses during development, which overturned the established theory that synapses are highly stable once they are formed. Live imaging of synapses also demonstrated that the molecular composition of synapses changes rapidly, driven by the rapid replacement of synaptic molecules. Fluorescence measurement of single GFP molecules enabled estimation of the absolute number of postsynaptic molecules in a single synapse. Furthermore, in multiple mouse models of autism spectrum disorders (ASDs), enhanced synapse turnover was detected as a common circuit-level phenotype. This study provides solid experimental evidence that an increase in synapse dynamics underlies the pathophysiology in mouse models of ASDs. The introduction of fluorescence imaging in neurobiology revealed that the neuronal cytoskeleton and synaptic structure are not static but dynamic cellular components. Imaging technology is expected to further advance our understanding of the dynamic properties of neurons and neural circuits.

Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: Obligatory role of hippocampal GPR55 receptors

Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.

Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway.

According to reports, prenatal exposure to valproic acid can induce autism spectrum disorder (ASD)-like symptoms in both humans and rodents. However, the exact cause and therapeutic method of ASD is not fully understood. Agmatine (AGM) is known for its neuroprotective effects, and this study aims to explore whether giving agmatine hydrochloride before birth can prevent autism-like behaviors in mouse offspring exposed prenatally to valproic acid. In this study, we investigated the effects of AGM prenatally on valproate (VPA)-exposed mice. We established a mouse model of ASD by prenatally administering VPA. From birth to weaning, we evaluated mouse behavior using the marble burying test, open-field test, and three-chamber social interaction test on male offspring. The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

Resolving neuroinflammatory and social deficits in ASD model mice: Dexmedetomidine downregulates NF-κB/IL-6 pathway via α2AR

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals’ daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.

Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor.

Recent studies have consistently demonstrated that the regulation of chromatin and gene transcription plays a pivotal role in the pathogenesis of neurodevelopmental disorders. Among many genes involved in these pathways, KMT2C, encoding one of the six known histone H3 lysine 4 (H3K4) methyltransferases in humans and rodents, was identified as a gene whose heterozygous loss-of-function variants are causally associated with autism spectrum disorder (ASD) and the Kleefstra syndrome phenotypic spectrum. However, little is known about how KMT2C haploinsufficiency causes neurodevelopmental deficits and how these conditions can be treated. To address this, we developed and analyzed genetically engineered mice with a heterozygous frameshift mutation of Kmt2c (Kmt2c+/fs mice) as a disease model with high etiological validity. In a series of behavioral analyses, the mutant mice exhibit autistic-like behaviors such as impairments in sociality, flexibility, and working memory, demonstrating their face validity as an ASD model. To investigate the molecular basis of the observed abnormalities, we performed a transcriptomic analysis of their bulk adult brains and found that ASD risk genes were specifically enriched in the upregulated differentially expressed genes (DEGs), whereas KMT2C peaks detected by ChIP-seq were significantly co-localized with the downregulated genes, suggesting an important role of putative indirect effects of Kmt2c haploinsufficiency. We further performed single-cell RNA sequencing of newborn mouse brains to obtain cell type-resolved insights at an earlier stage. By integrating findings from ASD exome sequencing, genome-wide association, and postmortem brain studies to characterize DEGs in each cell cluster, we found strong ASD-associated transcriptomic changes in radial glia and immature neurons with no obvious bias toward upregulated or downregulated DEGs. On the other hand, there was no significant gross change in the cellular composition. Lastly, we explored potential therapeutic agents and demonstrate that vafidemstat, a lysine-specific histone demethylase 1 (LSD1) inhibitor that was effective in other models of neuropsychiatric/neurodevelopmental disorders, ameliorates impairments in sociality but not working memory in adult Kmt2c+/fs mice. Intriguingly, the administration of vafidemstat was shown to alter the vast majority of DEGs in the direction to normalize the transcriptomic abnormalities in the mutant mice (94.3 and 82.5% of the significant upregulated and downregulated DEGs, respectively, P < 2.2 × 10-16, binomial test), which could be the molecular mechanism underlying the behavioral rescuing. In summary, our study expands the repertoire of ASD models with high etiological and face validity, elucidates the cell-type resolved molecular alterations due to Kmt2c haploinsufficiency, and demonstrates the efficacy of an LSD1 inhibitor that might be generalizable to multiple categories of psychiatric disorders along with a better understanding of its presumed mechanisms of action.

Alterations of Perineuronal Net Expression and Abnormal Social Behavior and Whisker-dependent Texture Discrimination in Mice Lacking the Autism Candidate Gene Engrailed 2

GABAergic interneurons and perineuronal nets (PNNs) are important regulators of plasticity throughout life and their dysfunction has been implicated in the pathogenesis of several neuropsychiatric conditions, including autism spectrum disorders (ASD). PNNs are condensed portions of the extracellular matrix (ECM) that are crucial for neural development and proper formation of synaptic connections.We previously showed a reduced expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of adult mice lacking the Engrailed2 gene (En2-/- mice), a mouse model of ASD. Since alterations in PNNs have been proposed as a possible pathogenic mechanism in ASD, we hypothesized that the PNN dysfunction may contribute to the neural and behavioral abnormalities of En2-/- mice. Here, we show an increase in the PNN fluorescence intensity, evaluated by Wisteria floribunda agglutinin, in brain regions involved in social behavior and somatosensory processing. In addition, we found that En2-/- mice exhibit altered texture discrimination through whiskers and display a marked decrease in the preference for social novelty.Our results raise the possibility that altered expression of PNNs, together with defects of GABAergic interneurons, might contribute to the pathogenesis of social and sensory behavioral abnormalities.

"Therapeutic potential of licorice extract in a prenatal valproic acid model of autism spectrum disorder in Wistar rats: Neurobehavioral and neurobiochemical insights"

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), impose significant burdens on society due to their genetic and clinical complexity. We explored the therapeutic potential of Glycyrrhiza glabra (licorice) extract in a prenatal valproic acid (VPA) model of ASD. Neurobehavioral parameters encompassing social interaction, locomotor activity, repetitive behaviour, anxiety-related behaviour, and learning and memory were assessed in Wistar rat offspring. Licorice extract administration at 150 mg/kg and 300 mg/kg was initiated from postnatal day 21, emulating the developmental stage of early childhood. The study incorporated a controlled group, a VPA-induced ASD group, and groups treated with two different doses of licorice extract and Risperidone.Results revealed that licorice extract, particularly at 300 mg/kg, exhibited remarkable potential in restoring social interaction deficits, enhancing locomotor activity, attenuating repetitive behaviour, and mitigating anxiety-related behaviour-like behaviours. Furthermore, licorice extract displayed cognitive benefits, as evidenced by the discrimination index enhancement in object recognition memory. Importantly, licorice extract demonstrated modulatory effects on neuroinflammation and oxidative stress, evident through suppressed interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels, as well as reduced thiobarbaturic acid reactive substances (TBARS) in the brain.These findings underscore the promising neuroprotective properties of Glycyrrhiza glabra extract against prenatal VPA-induced ASD-like behaviours. The elucidation of licorice's multifaceted impact on behaviour, cognition, and neurobiochemical markers offers a potential avenue for future therapeutic interventions for ASD, meriting further investigation in clinical contexts. This study contributes to the expanding knowledge of natural compounds in ameliorating complex neurodevelopmental disorders and highlights the necessity of multi-faceted approaches to address their intricate etiology and manifestation.

Exploratory Analysis of MicroRNA Alterations in a Neurodevelopmental Mouse Model for Autism Spectrum Disorder and Schizophrenia.

MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression levels and have been implicated in the pathogenesis of autism spectrum disorder (ASD) and schizophrenia (SCZ). In this study, we examined the adult expression profiles of specific miRNAs in the prefrontal cortex (PFC) of a neurodevelopmental mouse model for ASD and SCZ that mimics perinatal pathology, such as NMDA receptor hypofunction, and exhibits behavioral and neurophysiological phenotypes related to these disorders during adulthood. To model the early neuropathogenesis of the disorders, mouse pups were administered subcutaneously with ketamine (30 mg/Kg) at postnatal days 7, 9, and 11. We focused on a set of miRNAs most frequently altered in ASD (miR-451a and miR-486-3p) and in SCZ (miR-132-3p and miR-137-3p) according to human studies. Additionally, we explored miRNAs whose alterations have been identified in both disorders (miR-21-5p, miR-92a-2-5p, miR-144-3p, and miR-146a-5p). We placed particular emphasis on studying the sexual dimorphism in the dynamics of these miRNAs. Our findings revealed significant alterations in the PFC of this ASD- and SCZ-like mouse model. Specifically, we observed upregulated miR-451a and downregulated miR-137-3p. Furthermore, we identified sexual dimorphism in the expression of miR-132-3p, miR-137-3p, and miR-92a-2-5p. From a translational perspective, our results emphasize the potential involvement of miR-92a-2-5p, miR-132-3p, miR-137-3p, and miR-451a in the pathophysiology of ASD and SCZ and strengthen their potential as biomarkers and therapeutic targets of such disorders.

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by deficient social communication and interaction together with restricted, stereotyped behaviors. Currently approved treatments relieve comorbidities rather than core symptoms. Since excitation/inhibition balance and synaptic plasticity are disrupted in ASD, molecules targeting excitatory synaptic transmission appear as highly promising candidates to treat this pathology. Among glutamatergic receptors, the NMDA receptor has received particular attention through the last decade to develop novel allosteric modulators. Here, we show that positive NMDA receptor modulation by zelquistinel, a spirocyclic β-lactam platform chemical, relieves core symptoms in two genetic and one environmental mouse models of ASD. A single oral dose of zelquistinel rescued, in a dose-response manner, social deficits and stereotypic behavior in Shank3Δex13-16−/− mice while chronic intraperitoneal administration promoted a long-lasting relief of such autistic-like features in these mice. Subchronic oral mid-dose zelquistinel treatment demonstrated durable effects in Shank3Δex13-16−/−, Fmr1−/− and in utero valproate-exposed mice. Carry-over effects were best maintained in the Fmr1 null mouse model, with social parameters being still fully recovered two weeks after treatment withdrawal. Among recently developed NMDA receptor subunit modulators, zelquistinel displays a promising therapeutic potential to relieve core symptoms in ASD patients, with oral bioavailability and long-lasting effects boding well for clinical applications. Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD.

Bioenergetic signatures of neurodevelopmental regression.

Background: Studies have linked autism spectrum disorder (ASD) to physiological abnormalities including mitochondrial dysfunction. Mitochondrial dysfunction may be linked to a subset of children with ASD who have neurodevelopmental regression (NDR). We have developed a cell model of ASD which demonstrates a unique mitochondrial profile with mitochondrial respiration higher than normal and sensitive to physiological stress. We have previously shown similar mitochondrial profiles in individuals with ASD and NDR. Methods: Twenty-six ASD individuals without a history of NDR (ASD-NoNDR) and 15 ASD individuals with a history of NDR (ASD-NDR) were recruited from 34 families. From these families, 30 mothers, 17 fathers and 5 typically developing (TD) siblings participated. Mitochondrial respiration was measured in peripheral blood mononuclear cells (PBMCs) with the Seahorse 96 XF Analyzer. PBMCs were exposed to various levels of physiological stress for 1h prior to the assay using 2,3-dimethoxy-1,4-napthoquinone. Results: ASD-NDR children were found to have higher respiratory rates with mitochondria that were more sensitive to physiological stress as compared to ASD-NoNDR children, similar to our cellular model of NDR. Differences in mitochondrial respiration between ASD-NDR and TD siblings were similar to the differences between ASD-NDR and ASD-NoNDR children. Interesting, parents of children with ASD and NDR demonstrated patterns of mitochondrial respiration similar to their children such that parents of children with ASD and NDR demonstrated elevated respiratory rates with mitochondria that were more sensitive to physiological stress. In addition, sex differences were seen in ASD children and parents. Age effects in parents suggested that mitochondria of older parents were more sensitive to physiological stress. Conclusion: This study provides further evidence that children with ASD and NDR may have a unique type of mitochondrial physiology that may make them susceptible to physiological stressors. Identifying these children early in life before NDR occurs and providing treatment to protect mitochondrial physiology may protect children from experiencing NDR. The fact that parents also demonstrate mitochondrial respiration patterns similar to their children implies that this unique change in mitochondrial physiology may be a heritable factor (genetic or epigenetic), a result of shared environment, or both.

Yigansan ameliorates maternal immune activation-induced autism-like behaviours by regulating the IL-17A/TRAF6/MMP9 pathway: Network analysis and experimental validation

BackgroundMaternal immune activation (MIA) is a significant factor inducing to autism spectrum disorder (ASD) in offspring. The fundamental principle underlying MIA is that inflammation during pregnancy impedes fetal brain development and triggers behavioural alterations in offspring. The intricate pathogenesis of ASD renders drug treatment effects unsatisfactory. Traditional Chinese medicine has strong potential due to its multiple therapeutic targets. Yigansan, composed of seven herbs, is one of the few that has been proven to be effective in treating neuro-psychiatric disorders among numerous traditional Chinese medicine compounds, but its therapeutic effect on ASD remains unknown. HypothesisYigansan improves MIA-induced ASD-like behaviours in offspring by regulating the IL-17 signalling pathway. MethodsPregnant C57BL/6J mice were intraperitoneally injected with poly(I:C) to construct MIA models and offspring ASD models. Network analysis identified that the IL-17A/TRAF6/MMP9 pathway is a crucial pathway, and molecular docking confirmed the binding affinity between the monomer of Yigansan and target proteins. qRT-PCR and Western blot were used to detect the expression levels of inflammatory factors and pathway proteins, immunofluorescence was used to detect the distribution of IL-17A, and behavioural tests were used to evaluate the ASD-like behaviours of offspring. ResultsWe demonstrated that Yigansan can effectively alleviate MIA-induced neuroinflammation of adult offspring by regulating the IL-17A/TRAF6/MMP9 pathway, and the expression of IL-17A was reduced in the prefrontal cortex. Importantly, ASD-like behaviours have been significantly improved. Moreover, we identified that quercetin is the effective monomer for Yigansan to exert therapeutic effects. ConclusionOverall, this study was firstly to corroborate the positive therapeutic effect of Yigansan in the treatment of ASD. We elucidated the relevant molecular mechanism and regulatory pathway involved, determined the optimal therapeutic dose and effective monomer, providing new solutions for the challenges of drug therapy for ASD.

Female mice prenatally exposed to valproic acid exhibit complex and prolonged social behavior deficits

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and interests with a male to female bias of 4.2/1. Social behavior in ASD animal models is commonly analyzed in males, and seldomly in females, using the widely implemented three-chambers test procedure. Here, we implemented a novel procedure, the Live Mouse Tracker (LMT), combining artificial intelligence, machine learning procedures and behavioral measures. We used it on mice that were prenatally exposed to valproic acid (VPA) (450 mg/kg) at embryonic day 12.5, a widely recognized and potent ASD model that we had previously extensively characterized. We focused on female mice offspring, in which social deficits have been rarely documented when using the 3-CT procedure. We recorded several parameters related to social behavior in these mice, continuously for three days in groups of four female mice. Comparisons were made on groups of 4 female mice with the same treatment (4 saline or 4 VPA) or with different treatments (3 saline and 1 VPA). We report that VPA females show several types of social deficits, which are different in nature and magnitude in relation with time. When VPA mice were placed in the LMT alongside saline mice, their social deficits showed significant improvement as early as 1 h from the start of the experiment, lasting up to 3 days throughout the duration of the experiment. Our findings suggest that ASD may be underdiagnosed in females. They also imply that ASD-related social deficits can be ameliorated by the presence of typical individuals.

The developmental timing of spinal touch processing alterations predicts behavioral changes in genetic mouse models of autism spectrum disorders

Altered somatosensory reactivity is frequently observed among individuals with autism spectrum disorders (ASDs). Here, we report that although multiple mouse models of ASD exhibit aberrant somatosensory behaviors in adulthood, some models exhibit altered tactile reactivity as early as embryonic development, whereas in others, altered reactivity emerges later in life. Additionally, tactile overreactivity during neonatal development is associated with anxiety-like behaviors and social behavior deficits in adulthood, whereas tactile overreactivity that emerges later in life is not. The locus of circuit disruption dictates the timing of aberrant tactile behaviors, as altered feedback or presynaptic inhibition of peripheral mechanosensory neurons leads to abnormal tactile reactivity during neonatal development, whereas disruptions in feedforward inhibition in the spinal cord lead to touch reactivity alterations that manifest later in life. Thus, the developmental timing of aberrant touch processing can predict the manifestation of ASD-associated behaviors in mouse models, and differential timing of sensory disturbance onset may contribute to phenotypic diversity across individuals with ASD.

Insulin-like growth factor 2 (IGF-2) rescues social deficits in NLG3-/y mouse model of ASDs.

Autism spectrum disorders (ASDs) comprise developmental disabilities characterized by impairments of social interaction and repetitive behavior, often associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASDs symptomatology; thus, identifying novel therapies is urgently needed. Here, we used the Neuroligin 3 knockout mouse (NLG3-/y), a model that recapitulates the social deficits reported in ASDs patients, to test the effects of systemic administration of IGF-2, a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-2 treatment reverses the typical defects in social interaction and social novelty discrimination reflective of ASDs-like phenotypes. This effect was not accompanied by any change in spontaneous glutamatergic synaptic transmission in CA2 hippocampal region, a mechanism found to be crucial for social novelty discrimination. However, in both NLG3+/y and NLG3-/y mice IGF-2 increased cell excitability. Although further investigation is needed to clarify the cellular and molecular mechanisms underpinning IGF-2 effect on social behavior, our findings highlight IGF-2 as a potential pharmacological tool for the treatment of social dysfunctions associated with ASDs.

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats

BackgroundIndividuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats.MethodsIn vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains.ResultsOur results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered.ConclusionsThese results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Social Behavior in Animal Models of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and stereotyped, repetitive patterns of behaviors, limited interests, and cognitive impairment. Especially, social deficit has been considered a core feature of ASD. Because of the limitations of the experimental approach in humans, valid animal models are essential in an effort to identify novel therapeutics for social deficits in ASD. The genetic and environmental factors are clinically relevant to the pathophysiology of ASD. Epidemiological studies demonstrate environmental interventions such as prenatal exposure to valproic acid (VPA). Prenatal exposure to VPA represents a robust model of ASD exhibiting face, construct, and predictive validity. Here, we introduce protocols of the social interaction test and the three-chamber test for evaluating social deficits in mice prenatally exposed to VPA.

Разработка скрининговой шкалы для экспресс-диагностики риска расстройств аутистического спектра у детей трёх-четырёх лет

The article is devoted to a detailed description of the procedure and results of a scree­ning scale elaboration for rapid diagnosis of autism risk in Russian 3–4-year-olds. The study sample consisted of 926 children, of whom 383 were clinically diagnosed with ASD (autism spectrum disorder), 200 with DD (developmental delay), and 343 were from the Norm group. Using mathematical modeling methods, a 20-point scale of autism was constructed. The factor validity, reliability and effectiveness of the developed scale have been confirmed. The accuracy of the scale was 88.91% (sensitivity 92.1%, specificity 87.2%). The scale is based on 40 symptoms of autism, representing 4 vectors of its manifestation, 3 of which correspond to the main symptoms of autism according to DSM-5: "Emotional disorders", "Sensory disorders", "Communication disorders", but another dimension was also obtained called "Hyperactivity"/Disinhibition", which is unique for ASD models. The multigroup confirmatory factor analysis of structural and measurement equivalence confirmed the 4-vector structure of ASD&#x0D; for a sample of children with ASD, its structural and measurement invariance with respect to children with ASD differing in gender and age: boys and girls, 3- and 4-year-olds. However, for children without ASD, the existence of such a structure was not confirmed. Therefore, the selected scales reflect the autism vectors specific to children with ASD, according to which children with ASD differ from other children to the greatest extent.