Shared and divergent alteration of whole-brain connectivity and sensory deficits in multiple autism mouse models.

Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.

Behavioral phenotypes and neurobiological mechanisms in the Shank1 mouse model for autism spectrum disorder: A translational perspective

The family of SHANK proteins have been shown to be critical in regulating glutamatergic synaptic structure, function and plasticity. SHANK variants are also prevalent in autism spectrum disorders (ASDs), where glutamatergic synaptopathology has been shown to occur in multiple ASD mouse models. Our previous work has shown that dietary zinc in Shank3-/- and Tbr1+/- ASD mouse models can reverse or prevent ASD behavioural and synaptic deficits. Here, we have examined whether dietary zinc can influence behavioural and synaptic function in Shank2-/- mice. Our data show that dietary zinc supplementation can reverse hyperactivity and social preference behaviour in Shank2-/- mice, but it does not alter deficits in working memory. Consistent with this, at the synaptic level, deficits in NMDA/AMPA receptor-mediated transmission are also not rescued by dietary zinc. In contrast to other ASD models examined, we observed that SHANK3 protein was highly expressed at the synapses of Shank2-/- mice and that dietary zinc returned these to wild-type levels. Overall, our data show that dietary zinc has differential effectiveness in altering ASD behaviours and synaptic function across ASD mouse models even within the Shank family. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Developmental trajectory and sex differences in auditory processing in a PTEN-deletion model of autism spectrum disorders

Association Among Gut Microbes, Intestinal Physiology, and Autism

The dual-active histamine H3 receptor antagonist and acetylcholine esterase inhibitor E100 ameliorates stereotyped repetitive behavior and neuroinflammmation in sodium valproate induced autism in mice

PURPOSE: The first aim of this study is to change autistic behavior in Shank3B Knock-Out (KO) mice through treadmill exercise (TD), and the second aim is to alter SHANK protein receptors in the prefrontal cortex (PFC) of mice through TD.METHODS: Male mice were divided into Control (11-week-old, n=8), Control+TD (n=8), Shank3B KO (n=8), and Shank3B KO+TD (n=8). Control and Shank3B KO mice were exercised using TD for 2 weeks for 30 minutes each to observe the effects of exercise.RESULTS: Compared to the control group (C57BL/6J), Shank3B KO mice showed excessive self-grooming behavior; however, TD reduced repetitive behavior (<i>p</i><.05). The effect of TD was also seen in the behavior of Shank3B KO mice evaluated by measuring social interaction time using the two-chamber social behavior test and socio-sexual behavior test (<i>p</i><.05 compared to control). Differences were found in C57BL/6J and Shank3B KO mice by assessing proteins such as GluR2, Homer1, phosphorylated GSK-3α/β, and phosphorylated Akt1 in the PFC. The results suggested that TD yielded better outcomes in Shank3B KO+TD mice than in Shank3B KO mice.CONCLUSIONS: TD positively affected behavioral changes in repetitive behavior and social interaction defects in autism spectrum disorder (ASD) model mice. Alterations were also observed in the SHANK glutamate receptor and SHANK sub-signal transporter phosphorylation protein. This suggests that TD is an effective way to improve autistic behavior in ASD. However, further research is necessary to clarify the effects of TD by studying the underlying mechanisms and changes in SHANK proteins and other factors.

Social behavior is highly sensitive to brain network dysfunction caused by neuropsychiatric conditions like autism spectrum disorders (ASDs). Some studies suggest that autistic females show fewer social skill impairments than autistic males. However, the relationship between sex differences in social behavior and sexually dimorphic brain neurophysiology in ASD remains unclear. We hypothesize that sex-specific changes in cortical neurophysiology drive the sexual dimorphism observed in social behavior for ASD. To test this, we used male and female Tsc2+/- mice, a genetic ASD model, to examine cortical neuron morphology, the serotonergic system, E/I balance, structural connectivity, and social behavior. At the cellular level, transgenic males had shorter and less complex cortical basal dendrites, while transgenic females showed the opposite in apical dendrites. Notably, only Tsc2+/- females exhibited changes in the serotonergic system and E/I balance, with reduced cortical 5-HT1A receptor density and increased excitability. Additionally, activation of these serotonin receptors in transgenic animals correlated with E/I imbalance, highlighting inherent sexual dimorphisms in neuronal connectivity. In parallel, the TSC2 mouse model displayed sex-dependent changes in the structural connectivity of the cortex-amygdala-hippocampus circuit and social behavior: females showed a reduced number of axonal fiber pathways and reduced sociability, while males exhibited a loss of tissue density and deficits in social novelty. Moreover, in our ASD mouse model, better social performance correlated with the cortical serotonergic system. Our findings suggest that sex-dependent alterations in cortical neurophysiology, particularly in the serotonergic system, may contribute to the sexually dimorphic social behaviors observed in ASD.

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.

Autism spectrum disorder (ASD) is a heterogeneous syndrome characterized by behavioral features such as impaired social communication, repetitive behavior patterns, and a lack of interest in novel objects. A multimodal neuroimaging using magnetic resonance imaging (MRI) in patients with ASD shows highly heterogeneous abnormalities in function and structure in the brain associated with specific behavioral features. To elucidate the mechanism of ASD, several ASD mouse models have been generated, by focusing on some of the ASD risk genes. A specific behavioral feature of an ASD mouse model is caused by an altered gene expression or a modification of a gene product. Using these mouse models, a high field preclinical MRI enables us to non-invasively investigate the neuronal mechanism of the altered brain function associated with the behavior and ASD risk genes. Thus, MRI is a promising translational approach to bridge the gap between mice and humans. This review presents the evidence for multimodal MRI, including functional MRI (fMRI), diffusion tensor imaging (DTI), and volumetric analysis, in ASD mouse models and in patients with ASD and discusses the future directions for the translational study of ASD.

The development of biomarkers for psychiatric disorders is particularly challenging, given the frequent clinical heterogeneity, and the subjective nature of symptoms which requires finely tuned quantification methods for accurate diagnosis. Yet the more clinically heterogeneous a disease, the more valuable becomes an objective measure of disease state or severity. While identifying biological markers for psychiatric disorders has thus far remained out of reach, groundbreaking progress in DNA sequencing technologies and the completed human genome sequence have set the foundation for a novel perspective on clinical care, which also brings promising new approaches for biomarker discovery. The aim of genomic medicine [1] is to take advantage of the wealth of information encoded in an individual’s genome regarding their disease risk and potential responses to therapy. For diseases having significant contribution of genetic factors, the possibility to quantify genetic variation with enough depth is expected to lead to the development of effective markers of disease risk. This special issue of Disease Markers is dedicated to autism spectrum disorders (ASD) and discusses the current understanding of ASD genetics, as well as the possibilities of translating genetic research toward biomarker development in ASD. ASD are a spectrum of neurodevelopmental conditions characterized by language deficits, dysfunctions of social-reciprocal interactions and repetitiverestrictive behaviors. The clinical manifestations of autism are highly variable, both between individuals, and along an individual’s developmental trajectory. Although some individualswith ASD are highly functional, many are severely impaired and require permanent care. The significant level of impairment combined with the fact that no specific therapy is yet available for ASD, make ASD a devastating illness for patients and families, and a heavy financial burden for the healthcare system. The most effective intervention for ASD has proven to be early behavioral therapy [2]. Thus the identification of biological markers for ASD, allowing very early detection, even before the onset of symptoms, would be of tremendous value At the same time, one of the most well established characteristics of ASD is it’s high heritability, and significant research efforts have been geared toward understanding the genetic basis of autism. Thefield ofASD genetic research is still far from fully elucidating the mechanisms that govern ASD heritability, but the last two decades have undoubtedly brought about remarkable progress. Currently it is believed that both common genetic variation and rare DNA sequence variants contribute to the ASD genetic susceptibility [3], and that the relative contribution of common and rare alleles is variable among ASD cases. In the first article of this issue, “Mutant mouse models of autism spectrum disorders”, Yuri Bozzi and colleagues review the phenotypic characteristics of currently available mouse models of ASD as well as the contribution of mouse models toward the development of pharmacological therapy for ASD. Of particular importance for dissecting out the cellular and molecular mechanisms of ASD are several genes that have been identified as causes of genetic syndromes with a high incidence of ASD (FMR1, the gene mutated in fragile X syndrome, TSC1/TSC2, the genes responsible for tuberous sclerosis and NF1, the gene implicated in neurofibromatosis are just a few examples). Despite the

One of the most prevalent deficits in autism spectrum disorder (ASD) are sensitivities to sensory stimuli. Despite the prevalence of sensory deficits in autism, there are few paradigms capable of easily assessing sensory behaviors in ASD-like mouse models. We addressed this need by creating the Somatosensory Nose-poke Adapted Paradigm (SNAP), which consists of an elevated platform with 6 holes in the center, half of which are lined with sandpaper and half are smooth, requiring mice to use their whiskers to sense the texture. The SNAP paradigm assesses tactile sensory preferences as well as stereotypy, anxiety, and locomotion. We used two wild-type (neurotypical) mouse strains, C57BL/6J (C57) inbred and CD-1 outbred mice, and two ASD mouse models, BTBR (a model of idiopathic ASD) and Cntnap2 -/- mice (a model of syndromic ASD). We found that both ASD models produced more nose pokes into the rough condition than the smooth condition, suggesting an increased preference for complex tactile stimulation when compared with the neurotypical groups, wherein no differences were observed. Furthermore, we found increased stereotypy and time spent in the center, suggestive of decreased anxiety, only for BTBR mice compared with the other mouse strains. Overall, SNAP is an easy to implement task to assess the degree of preference for complex tactile stimulation in ASD mouse models that can be further modified to exclude possible confounding effects of novelty or anxiety on the sensory preferences.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and communication, along with restricted and repetitive behaviors. Both genetic and environmental factors contribute to ASD, with prenatal exposure to valproic acid (VPA) and nicotine being linked to increased risk. Impaired adult hippocampal neurogenesis, particularly in the ventral region, is thought to play a role in the social deficits observed in ASD. In this study, we investigated social behavior and adult hippocampal neurogenesis in C57BL/6J mice prenatally exposed to VPA or nicotine, as well as in genetically modified ASD models, including IQSEC2 knockout (KO) and NLGN3-R451C knock-in (KI) mice. Sociability and social novelty preference were evaluated using a three-chamber social interaction test. Adult hippocampal neurogenesis was assessed by BrdU and DCX immunofluorescence to identify newborn and immature neurons. VPA-exposed mice displayed significant deficits in social interaction, while nicotine-exposed mice exhibited mild impairment in social novelty preference. Both IQSEC2 KO and NLGN3-R451C KI mice demonstrated reduced adult neurogenesis, particularly in the ventral hippocampus, a region associated with social behavior and emotion. Across all ASD mouse models, a significant reduction in BrdU+/NeuN+ cells in the ventral hippocampus was observed, while dorsal hippocampal neurogenesis remained relatively unaffected. Similar reductions in DCX-positive cells were identified in VPA, nicotine, and NLGN3-R451C KI mice, indicating impaired proliferation or differentiation of neuronal progenitors. These findings suggest that impaired adult neurogenesis in the ventral hippocampus is a common hallmark across ASD mouse models and may underlie social behavior deficits. This study provides insight into region-specific neurogenic alterations linked to ASD pathophysiology and highlights potential targets for therapeutic interventions.

One unifying explanation for the complexity of Autism Spectrum Disorders (ASD) may lie in the disruption of excitatory/inhibitory (E/I) circuit balance during critical periods of development. We examined whether Parvalbumin (PV)-positive inhibitory neurons, which normally drive experience-dependent circuit refinement (Hensch Nat Rev Neurosci 6:877–888, 1), are disrupted across heterogeneous ASD mouse models. We performed a meta-analysis of PV expression in previously published ASD mouse models and analyzed two additional models, reflecting an embryonic chemical insult (prenatal valproate, VPA) or single-gene mutation identified in human patients (Neuroligin-3, NL-3 R451C). PV-cells were reduced in the neocortex across multiple ASD mouse models. In striking contrast to controls, both VPA and NL-3 mouse models exhibited an asymmetric PV-cell reduction across hemispheres in parietal and occipital cortices (but not the underlying area CA1). ASD mouse models may share a PV-circuit disruption, providing new insight into circuit development and potential prevention by treatment of autism.Electronic supplementary materialThe online version of this article (doi:10.1007/s11689-009-9023-x) contains supplementary material, which is available to authorized users.

From the Early Emergence of Psychiatry to Stem Cells and Neural Organoids.