The contributions of rare inherited and polygenic risk to ASD in multiplex families.

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.

An N-terminal and ankyrin repeat domain interactome of Shank3 identifies the protein complex with the splicing regulator Nono in mice.

An autism-associated gene Shank3 encodes multiple splicing isoforms, Shank3a-f. We have recently reported that Shank3a/b-knockout mice were more susceptible to kainic acid-induced seizures than wild-type mice at 4 weeks of age. Little is known, however, about how the N-terminal and ankyrin repeat domains (NT-Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry-based proteomic search for proteins interacting with GFP-tagged NT-Ank. In this study, NT-Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA-binding (n = 102), spliceosome (n = 22), and ribosome-associated molecules (n = 9) were significantly enriched. Among them, an X-linked intellectual disability-associated protein, Nono, was identified as a NT-Ank-binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b-knockout mice aberrantly expressed splicing isoforms of autism-associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA-binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism-associated genes after birth.

Speech Reception in Young Children with Autism Is Selectively Indexed by a Neural Oscillation Coupling Anomaly.

Communication difficulties are one of the core criteria in diagnosing autism spectrum disorder (ASD), and are often characterized by speech reception difficulties, whose biological underpinnings are not yet identified. This deficit could denote atypical neuronal ensemble activity, as reflected by neural oscillations. Atypical cross-frequency oscillation coupling, in particular, could disrupt the joint tracking and prediction of dynamic acoustic stimuli, a dual process that is essential for speech comprehension. Whether such oscillatory anomalies already exist in very young children with ASD, and with what specificity they relate to individual language reception capacity is unknown. We collected neural activity data using electroencephalography (EEG) in 64 very young children with and without ASD (mean age 3; 17 females, 47 males) while they were exposed to naturalistic-continuous speech. EEG power of frequency bands typically associated with phrase-level chunking (δ, 1-3 Hz), phonemic encoding (low-γ, 25-35 Hz), and top-down control (ß, 12-20 Hz) were markedly reduced in ASD relative to typically developing (TD) children. Speech neural tracking by δ and θ (4-8 Hz) oscillations was also weaker in ASD compared with TD children. After controlling gaze-pattern differences, we found that the classical θ/γ coupling was replaced by an atypical ß/γ coupling in children with ASD. This anomaly was the single most specific predictor of individual speech reception difficulties in ASD children. These findings suggest that early interventions (e.g., neurostimulation) targeting the disruption of ß/γ coupling and the upregulation of θ/γ coupling could improve speech processing coordination in young children with ASD and help them engage in oral interactions.SIGNIFICANCE STATEMENT Very young children already present marked alterations of neural oscillatory activity in response to natural speech at the time of autism spectrum disorder (ASD) diagnosis. Hierarchical processing of phonemic-range and syllabic-range information (θ/γ coupling) is disrupted in ASD children. Abnormal bottom-up (low-γ) and top-down (low-ß) coordination specifically predicts speech reception deficits in very young ASD children, and no other cognitive deficit.

Tactile sensory processing deficits in genetic mouse models of autism spectrum disorder.

Altered sensory processing is a common feature in autism spectrum disorder (ASD), as recognized in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Although altered responses to tactile stimuli are observed in over 60% of individuals with ASD, the neurobiological basis of this phenomenon is poorly understood. ASD has a strong genetic component and genetic mouse models can provide valuable insights into the mechanisms underlying tactile abnormalities in ASD. This review critically addresses recent findings regarding tactile processing deficits found in mouse models of ASD, with a focus on behavioral, anatomical, and functional alterations. Particular attention was given to cellular and circuit-level functional alterations, both in the peripheral and central nervous systems, with the objective of highlighting possible convergence mechanisms across models. By elucidating the impact of mutations in ASD candidate genes on somatosensory circuits and correlating them with behavioral phenotypes, this review significantly advances our understanding of tactile deficits in ASD. Such insights not only broaden our comprehension but also pave the way for future therapeutic interventions.

Patient-specific mutation of Dync1h1 in mice causes brain and behavioral deficits.

AIMS: Cytoplasmic dynein heavy chain (DYNC1H1) is a multi-subunit protein complex that provides motor force for movement of cargo on microtubules and traffics them back to the soma. In humans, mutations along the DYNC1H1 gene result in intellectual disabilities, cognitive delays, and neurologic and motor deficits. The aim of the study was to generate a mouse model to a newly identified de novo heterozygous DYNC1H1 mutation, within a functional ATPase domain (c9052C > T(P3018S)), identified in a child with motor deficits, and intellectual disabilities. RESULTS: P3018S heterozygous (HET) knockin mice are viable; homozygotes are lethal. Metabolic and EchoMRI™ testing show that HET mice have a higher metabolic rate, are more active, and have less body fat compared to wildtype mice. Neurobehavioral studies show that HET mice perform worse when traversing elevated balance beams, and on the negative geotaxis test. Immunofluorescent staining shows neuronal migration abnormalities in the dorsal and lateral neocortex with heterotopia in layer I. Neuron-subtype specific transcription factors CUX1 and CTGF identified neurons from layers II/III and VI respectively in cortical layer I, and abnormal pyramidal neurons with MAP2+ dendrites projecting downward from the pial surface. CONCLUSION: The HET mice are a good model for the motor deficits seen in the child, and highlights the importance of cytoplasmic dynein in the maintenance of cortical function and dendritic orientation relative to the pial surface. Our results are discussed in the context of other dynein mutant mice and in relation to clinical presentation in humans with DYNC1H1 mutations.

Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders.

Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.

Cerebellar Roles in Motor and Social Functions and Implications for ASD.

The cerebellum, traditionally linked to voluntary motor coordination, is now recognized for its role in nonmotor functions, including cognitive and social behaviors. This expanded understanding is vital for identifying neurodevelopmental disorders such as autism spectrum disorder (ASD), where cerebellar abnormalities are common. Recent research has identified specific cerebellar circuits contributing to these diverse functions, revealing interconnected pathways that regulate both motor and social behaviors. The cerebellum communicates extensively with the cerebral cortex, thalamus, and limbic structures through converging and diverging pathways, integrating sensory and motor information to fine-tune outputs and influence higher-order functions. Mouse models have been instrumental in dissecting cerebellar functions, with studies using genetic and neuroanatomical techniques to manipulate specific circuits and observe behavioral outcomes. Disruptions in cerebellar pathways can lead to motor deficits and social impairments, mirroring human neurodevelopmental disorders. This review explores the anatomical and functional organization of cerebellar pathways in mice, their role in behavior, and the implications of cerebellar dysfunction in disorders such as ASD. Understanding these pathways enhances knowledge of cerebellar contributions to behavior and informs therapeutic strategies for cerebellar and neurodevelopmental disorders, emphasizing the integral role of the cerebellum in motor and social functions.

The influence of asthma on neuroinflammation and neurodevelopment: From epidemiology to basic models.

Asthma is a highly heterogeneous inflammatory disease that can have a significant effect on both the respiratory system and central nervous system. Population based studies and animal models have found asthma to be comorbid with a number of neurological conditions, including depression, anxiety, and neurodevelopmental disorders. In addition, maternal asthma during pregnancy has been associated with neurodevelopmental disorders in the offspring, such as autism spectrum disorders and attention deficit hyperactivity disorder. In this article, we review the most current epidemiological studies of asthma that identify links to neurological conditions, both as it relates to individuals that suffer from asthma and the impacts asthma during pregnancy may have on offspring neurodevelopment. We also discuss the relevant animal models investigating these links, address the gaps in knowledge, and explore the potential future directions in this field.

Loss of interleukin 1 signaling causes impairment of microglia- mediated synapse elimination and autistic-like behaviour in mice.

In the last years, the hypothesis that elevated levels of proinflammatory cytokines contribute to the pathogenesis of neurodevelopmental diseases has gained popularity. IL-1 is one of the main cytokines found to be elevated in Autism spectrum disorder (ASD), a complex neurodevelopmental condition characterized by defects in social communication and cognitive impairments. In this study, we demonstrate that mice lacking IL-1 signaling display autistic-like defects associated with an excessive number of synapses. We also show that microglia lacking IL-1 signaling at early neurodevelopmental stages are unable to properly perform the process of synapse engulfment and display excessive activation of mammalian target of rapamycin (mTOR) signaling. Notably, even the acute inhibition of IL-1R1 by IL-1Ra is sufficient to enhance mTOR signaling and reduce synaptosome phagocytosis in WT microglia. Finally, we demonstrate that rapamycin treatment rescues the defects in IL-1R deficient mice. These data unveil an exclusive role of microglial IL-1 in synapse refinement via mTOR signaling and indicate a novel mechanism possibly involved in neurodevelopmental disorders associated with defects in the IL-1 pathway.

Associations of neighborhood greenspace, and active living environments with autism spectrum disorders: A matched case-control study in Ontario, Canada.

BACKGROUND: Increasing evidence links early life residential exposure to natural urban environmental attributes and positive health outcomes in children. However, few studies have focused on their protective effects on the risk of autism spectrum disorder (ASD). The aim of this study was to investigate the associations of neighborhood greenspace, and active living environments during pregnancy with ASD in young children (≤6 years). METHODS: We conducted a population-based matched case-control study of singleton term births in Ontario, Canada for 2012-2016. The ASD and environmental data was generated using the Ontario Autism Spectrum Profile, the Better Outcomes Registry & Network Ontario, and Canadian Urban Environmental Health Research Consortium. We employed conditional logistic regressions to estimate the odds ratio (OR) between ASD and environmental factors characterizing selected greenspace metrics and neighborhoods conducive to active living (i.e., green view index (GVI), normalized difference vegetation index (NDVI), tree canopy, park proximity and active living environments index (ALE)). RESULTS: We linked 8643 mother-child pairs, including 1554 cases (18%). NDVI (OR 1.034, 0.944-1.024, per Inter Quartile Range [IQR] = 0.08), GVI (OR 1.025, 95% CI 0.953-1.087, per IQR = 9.45%), tree canopy (OR 0.992, 95% CI 0.903-1.089, per IQR = 6.24%) and the different categories of ALE were not associated with ASD in adjusted models for air pollution. In contrast, living closer to a park was protective (OR 0.888, 0.833-0.948, per 0.06 increase in park proximity index), when adjusted for air pollution. CONCLUSIONS: This study reported mixed findings showing both null and beneficial effects of green spaces and active living environments on ASD. Further investigations are warranted to elucidate the role of exposure to greenspaces and active living environments on the development of ASD.

The psychological impact of the COVID-19 pandemic on children/adolescents with ASD and their family environment: a systematic review.

The main objective of the review is to analyze the impact of the pandemic in children/teenagers with Autism spectrum disorder (ASD) and in their family environment. An electronic search was carried out in different databases (PsycInfo, Web of Science and Scopus) in order to find publications associated with the aim of this project. The search terms used were derived from the combination of the following search string: "((Pandemic OR Epidemic OR Outbreak OR COVID-19 OR Coronavirus) AND (Children OR Adolescents OR Youth OR Child OR Teenager) AND (Autism OR ASD OR Autism Spectrum Disorder))''. In total, 21 articles were included in this review. The findings of the different investigations included in this review show that the pandemic has produced a negative psychological impact in children/teenagers with ASD. Therefore, long-term follow-up studies should be carried out with the objective of creating effective interventions to treat this problematical.

Using AI-Based Virtual Companions to Assist Adolescents with Autism in Recognizing and Addressing Cyberbullying.

Social media platforms and online gaming sites play a pervasive role in facilitating peer interaction and social development for adolescents, but they also pose potential threats to health and safety. It is crucial to tackle cyberbullying issues within these platforms to ensure the healthy social development of adolescents. Cyberbullying has been linked to adverse mental health outcomes among adolescents, including anxiety, depression, academic underperformance, and an increased risk of suicide. While cyberbullying is a concern for all adolescents, those with disabilities are particularly susceptible and face a higher risk of being targets of cyberbullying. Our research addresses these challenges by introducing a personalized online virtual companion guided by artificial intelligence (AI). The web-based virtual companion's interactions aim to assist adolescents in detecting cyberbullying. More specifically, an adolescent with ASD watches a cyberbullying scenario in a virtual environment, and the AI virtual companion then asks the adolescent if he/she detected cyberbullying. To inform the virtual companion in real time to know if the adolescent has learned about detecting cyberbullying, we have implemented fast and lightweight cyberbullying detection models employing the T5-small and MobileBERT networks. Our experimental results show that we obtain comparable results to the state-of-the-art methods despite having a compact architecture.

Schema therapy in adults with autism spectrum disorder: A scoping review.

BACKGROUND: Schema therapy (ST) in adults with autism spectrum disorder (ASD) have gained increasing interest in clinical practice and research. However, to date, there has been no synthesis of the literature on ST as treatment for adults with ASD. Through a scoping review, we aim to summarize the emerging research and literature on ST for adults with ASD. METHODS: A comprehensive literature search of three electronic databases was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Publications were included that examined ST in adults with ASD and non-clinical adults with autistic traits. RESULTS: Systematic searches identified a total of 11 publications, all published since 2014, with the majority being conducted by Dutch and Japanese researchers. Of the 11 publications, 1 described an ST-informed social interaction training, 1 was an ST protocol, 2 described conceptual ST models, 2 were case examples, 2 examined early maladaptive schemas (EMSs) and 3 investigated the effectiveness of ST interventions. In summary, the theoretical exploration, practical examples of the application of ST and research findings with preliminary evidence of ST, EMSs and schema modes (SMs) in adults with ASD point towards the potential of ST for the treatment of adults with ASD. DISCUSSION: The current scoping review highlights preliminary research findings and offers valuable suggestions for clinicians treating adults with ASD. This review underscores the need for development of and research in specialized ST protocols and programmes tailored to adults with ASD with chronic mental conditions, such as personality disorders (PDs).

Rates of maternal weight gain over the course of pregnancy and offspring risk of neurodevelopmental disorders.

BACKGROUND: Previous studies have suggested that gestational weight gain (GWG) outside an optimal range increases the risks of neurodevelopmental disorders (NDDs) in offspring including autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit/hyperactivity disorder (ADHD). The sequential development of the fetal brain suggests that its vulnerability may vary depending on the timing of exposure. Therefore, we aimed to investigate the associations of not only gestational age-standardized total GWG (GWG z-scores) but also the rate of GWG (RGWG) in the second and third trimesters with risks of NDDs in offspring. METHODS: In this population-based cohort study, we used maternal weight data from antenatal care records collected for 57,822 children born to 53,516 mothers between 2007 and 2010 in the Stockholm Youth Cohort. Children were followed from 2 years of age to December 31, 2016. GWG z-scores and RGWG (kg/week) in the second and third trimesters were considered as continuous variables in cox regression models, clustered on maternal identification numbers. Nonlinear relationships were accommodated using restricted cubic splines with 3 knots. RGWG were also categorized according to the 2009 US Institute of Medicine (IOM) guidelines for optimal GWG. According to the IOM guidelines, the optimal rate of GWG for the second and third trimesters for underweight, normal weight, overweight, and obese categories were 0.44-0.58, 0.35-0.50, 0.23-0.33, and 0.17-0.27 kg/week, respectively. RESULTS: During a mean follow-up of 5.4 years (until children were on average 7.4 years old), 2205 (3.8%) children were diagnosed with NDDs, of which 1119 (1.9%) received a diagnosis of ASD, 1353 (2.3%) ADHD, and 270 (0.5%) ID. We observed a J-shaped association between total GWG z-score and offspring risk of NDDs, with higher total GWG (GWG z-score = 2) associated with 19% increased risk of any NDD (95% CI = 3-37%) and lower total GWG (GWG z-score = - 2) associated with 12% increased risk of any NDDs (95% CI = 2-23%), compared to the reference (GWG z-score = 0). In the second trimester, lower RGWG (0.25 kg/week) was associated with a 9% increased risk of any NDD diagnosis (95% CI = 4-15%) compared to the median of 0.57 kg/week, with no apparent relationship between higher RGWG and risk of NDDs. In the third trimester, there was no apparent association between lower RGWG and risk of NDDs, though higher RGWG (1 kg/week) was associated with a 28% increased risk of NDD diagnosis (95% CI = 16-40%), compared to the median (0.51 kg/week). When considering categorized RGWG, we found that slow weight gain in the second trimester followed by rapid weight gain in the third trimester most significantly increased the risk of ADHD (HRadjusted = 1.55, 1.13-2.13) and ID (HRadjusted = 2.53, 1.15-5.55) in offspring. The main limitations of our study are the relatively few years for which detailed GWG data were available and the relatively short follow-up for the outcomes, limiting power to detect associations and misclassifying children who receive an NDD diagnosis later in childhood. CONCLUSIONS: The relationship between maternal weight gain and children's risk of NDDs varied according to timing in pregnancy, with the greatest risks associated with slow weight gain in the second trimester and rapid weight gain in the third trimester.

Characterizing the neuroimmune environment of offspring in a novel model of maternal allergic asthma and particulate matter exposure.

Inflammation during pregnancy is associated with an increased risk for neurodevelopmental disorders (NDD). Increased gestational inflammation can be a result of an immune condition/disease, exposure to infection, and/or environmental factors. Epidemiology studies suggest that cases of NDD are on the rise. Similarly, rates of asthma are increasing, and the presence of maternal asthma during pregnancy increases the likelihood of a child being later diagnosed with NDD such as autism spectrum disorders (ASD). Particulate matter (PM), via air pollution, is an environmental factor known to worsen the symptoms of asthma, but also, PM has been associated with increased risk of neuropsychiatric disorders. Despite the links between asthma and PM with neuropsychiatric disorders, there is a lack of laboratory models investigating combined prenatal exposure to asthma and PM on offspring neurodevelopment. Thus, we developed a novel mouse model that combines exposure to maternal allergic asthma (MAA) and ultrafine iron-soot (UIS), a common component of PM. In the current study, female BALB/c mice were sensitized for allergic asthma with ovalbumin (OVA) prior to pregnancy. Following mating and beginning on gestational day 2 (GD2), dams were exposed to either aerosolized OVA to induce allergic asthma or phosphate buffered saline (PBS) for 1 h. Following the 1-h exposure, pregnant females were then exposed to UIS with a size distribution of 55 to 169 nm at an average concentration of 176 ± 45 µg/m3) (SD), or clean air for 4 h, over 8 exposure sessions. Offspring brains were collected at postnatal days (P)15 and (P)35. Cortices and hippocampal regions were then isolated and assessed for changes in cytokines using a Luminex bead-based multiplex assay. Analyses identified changes in many cytokines across treatment groups at both timepoints in the cortex, including interleukin-1 beta (IL-1ß), and IL-17, which remained elevated from P15 to P35 in all treatment conditions compared to controls. There was a suppressive effect of the combined MAA plus UIS on the anti-inflammatory cytokine IL-10. Potentially shifting the cytokine balance towards more neuroinflammation. In the hippocampus at P15, elevations in cytokines were also identified across the treatment groups, namely IL-7. The combination of MAA and UIS exposure (MAA-UIS) during pregnancy resulted in an increase in microglia density in the hippocampus of offspring, as identified by IBA-1 staining. Together, these data indicate that exposure to MAA, UIS, and MAA-UIS result in changes in the neuroimmune environment of offspring that persist into adulthood.

Exploring the molecular mechanism of comorbidity of autism spectrum disorder and inflammatory bowel disease by combining multiple data sets.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is difficult to diagnose. Inflammatory bowel disease (IBD) is a common chronic digestive disease. Previous studies have shown a potential correlation between ASD and IBD, but the pathophysiological mechanism remains unclear. The purpose of this research was to examine the biological mechanisms underlying the differentially expressed genes (DEGs) of ASD and IBD using bioinformatics tools. METHODS: Limma software was used to evaluate the DEGs between ASD and IBD. The GSE3365, GSE18123, and GSE150115 microarray data sets were acquired from the Gene Expression Omnibus (GEO) database. We then performed 6 analyses, namely, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotation; weighted gene coexpression network analysis; correlation analysis of hub genes with autophagy, ferroptosis and immunity; transcriptional regulation analysis of hub genes; single-cell sequencing analysis; and potential therapeutic drug prediction. RESULTS: A total of 505 DEGs associated with ASD and 616 DEGs associated with IBD were identified, and 7 genes overlapped between these sets. GO and KEGG analyses revealed several pathways enriched in both diseases. A total of 98 common genes related to ASD and IBD were identified by weighted gene coexpression network analysis (WGCNA), and 4 hub genes were obtained by intersection with the 7 intersecting DEGs, which were PDGFC, CA2, GUCY1B3 and SDPR. We also found that 4 hub genes in the two diseases were related to autophagy, ferroptosis or immune factors. In addition, motif-TF annotation analysis showed that cisbp__M0080 was the most relevant motif. We also used the Connectivity Map (CMap) database to identify 4 potential therapeutic agents. CONCLUSION: This research reveals the shared pathogenesis of ASD and IBD. In the future, these common hub genes may provide new targets for further mechanistic research as well as new therapies for patients with ASD and IBD.

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.

Effects of extended-release 7-nitroindazole gel formulation treatment on the behavior of Shank3 mouse model of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral deficits such as abnormalities in communication, social interaction, anxiety, and repetitive behavior. We have recently shown that the Shank3 mutation in mice representing a model of ASD causes excessive nitric oxide (NO) levels and aberrant protein S-nitrosylation. Further, 10-day daily injections of 7-NI, a neuronal nitric oxide synthase inhibitor, into Shank3Δ4-22 and Cntnap2(-/-) mutant mice (models of ASD) at a dose of 80 mg/kg reversed the manifestations of ASD phenotype. In this study, we proposed an extended release of 7-NI using a novel drug system. Importantly, unlike the intraperitoneal injections, our new preparation of poly (sebacic acid-co-ricinoleic acid) (PSARA) gel containing 7-NI was injected subcutaneously into the mutant mice only once. The animals underwent behavioral testing starting from day 3 post-injection. It should be noted that the developed PSARA gel formulation allowed a slow release of 7-NI maintaining the plasma level of the drug at ∼45 µg/ml/day. Further, we observed improved memory and social interaction and reduced anxiety-like behavior in Shank3 mutant mice. This was accompanied by a reduction in 3-nitrotyrosine levels (an indicator of nitrative/nitrosative stress) in plasma. Overall, we suggest that our single-dose formulation of PSARA gel is very efficient in rendering a therapeutic effect of 7-NI for at least 10 days. This approach may provide in the future a rational design of an effective ASD treatment using 7-NI and its clinical translation.

Autism Spectrum Disorder and auditory sensory alterations: a systematic review on the integrity of cognitive and neuronal functions related to auditory processing.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a wide spectrum of symptoms, mainly characterized by social, communication, and cognitive impairments. Latest diagnostic criteria according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, 2013) now include sensory issues among the four restricted/repetitive behavior features defined as "hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment". Here, we review auditory sensory alterations in patients with ASD. Considering the updated diagnostic criteria for ASD, we examined research evidence (2015-2022) of the integrity of the cognitive function in auditory-related tasks, the integrity of the peripheral auditory system, and the integrity of the central nervous system in patients diagnosed with ASD. Taking into account the different approaches and experimental study designs, we reappraise the knowledge on auditory sensory alterations and reflect on how these might be linked with behavior symptomatology in ASD.

A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report.

INTRODUCTION: NEUROG1 gene is yet to be associated with a set of human phenotypes in the OMIM database. Three cases have previously been diagnosed with cranial dysinnervation due to biallelic variants in the NEUROG1 gene. This is the fourth and a novel report of a sibling pair harboring a homozygous variant in the NEUROG1 gene with autism as an additional phenotype. A brief review of the literature in conjunction with a genotype-phenotype correlation has been described. A potential hypothesis for the presence of the autistic phenotype in the present case has also been elucidated. CASE PRESENTATION: A female aged 6 years and 9 months born to endogamous and phenotypically healthy parents was diagnosed with global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her MRI of the brain revealed mild peritrigonal white matter hyperintensity, and MRI and CT scan of the temporal bones showed abnormal cranial nerves. The proband's younger sister, aged 4-years, was similarly affected. Whole exome sequencing was performed in the proband, which revealed a novel homozygous, likely pathogenic, truncating frameshift variant, c.228_231dup (p.Thr78ProfsTer122) in exon 1 of the NEUROG1 gene (ENST00000314744.4). Segregation analysis by Sanger sequencing showed the proband and her younger sister to be homozygotes and their parents to be heterozygous carriers. CONCLUSION: This is the fourth report across the globe with a variant identified in the NEUROG1 gene to be associated with cranial dysinnervation phenotype. An additional phenotype of autism in two female siblings was a novel observation. We provide a hypothetical framework which could explain the pleiotropic effect of a dysfunctional NEUROG1 protein leading to autism and posit it as a candidate for diagnosis of autism spectrum disorder with congenital cranial dysinnervation disorder.