Summary The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency on brain development.

Human chromosome 16p11.2 microdeletion is among the most common gene copy number variations (CNVs) known to confer risk for intellectual disability (ID) and autism spectrum disorder (ASD) and affects an estimated 3 in 10 000 people. Caused by a single copy deletion of ~27 genes, 16p11.2 microdeletion syndrome is characterized by ID, impaired language, communication and socialization skills, and ASD. Studies in animal models where a single copy of the syntenic 16p11.2 region has been deleted have revealed morphological, behavioral, and electrophysiological abnormalities. Previous studies suggested the possibility of some overlap in the mechanisms of pathophysiology in 16p11.2 microdeletion syndrome and fragile X syndrome. Improvements in fragile X phenotypes have been observed following chronic treatment with R-baclofen, a selective agonist of GABAB receptors. We were therefore motivated to investigate the effects of chronic oral R-baclofen administration in two independently generated mouse models of 16p11.2 microdeletion syndrome. In studies performed across two independent laboratories, we found that chronic activation of GABAB receptors improved performance on a series of cognitive and social tasks known to be impaired in two different 16p11.2 deletion mouse models. Our findings suggest that R-baclofen may have clinical utility for some of the core symptoms of human 16p11.2 microdeletion syndrome.

SHANK3 is a synaptic scaffolding protein localized in the postsynaptic density and has a crucial role in synaptogenesis and neural physiology. Deletions and point mutations in SHANK3 cause Phelan–McDermid Syndrome (PMS), and have also been implicated in autism spectrum disorder (ASD) and intellectual disabilities, leading to the hypothesis that reduced SHANK3 expression impairs basic brain functions that are important for social communication and cognition. Several mouse models of Shank3 deletions have been generated, varying in the specific domain deleted. Here we report impairments in cognitive function in mice heterozygous for exon 13–16 (coding for the PDZ domain) deletion. The touchscreen pairwise discrimination task was chosen by virtue of its: (a) conceptual and technical similarities to the Cambridge Neuropsychological Test Automated Battery (CANTAB) and NIH Toolbox Cognition Battery used for testing cognitive functions in humans, (b) minimal demand on motor abilities, and (c) capability to measure many aspects of learning and memory and complex cognitive functions, including cognitive flexibility. The similarity between our mouse tasks and human cognitive assays means a high translational validity in future intervention studies using preclinical models. Our study revealed that Shank3B heterozygous mice (+/–) were slower to reach criterion in the pairwise visual discrimination task, and exhibited trends toward making more errors (first trial errors) and more correction errors than wildtype mice (+/+). Open field activity was normal in +/–, ruling out hypo- or hyperactivity as potential confounds in the touchscreen test. Sociability in the three chamber test was also normal in both +/+ and +/–. These results indicate a deficit in discrimination learning in the Shank3B model of PMS and ASD, suggesting that this mouse model is a useful preclinical tool for studying neurobiological mechanisms behind cognitive impairments in PMS and ASD. The current findings are the starting point for our future research in which we will investigate multiple domains of cognition and explore pharmacological interventions.

Purpose of Review This review aims to summarize the current body of behavioral, physiological, and molecular knowledge concerning tactile sensitivity in autism spectrum disorder (ASD), with a focus on recent studies utilizing rodent models. Recent Findings Mice with mutations in the ASD-related genes, Shank3, Fmr1, UBE3A, and Mecp2, display tactile abnormalities. Some of these abnormalities appear to be caused by mutation-related changes in the PNS, as opposed to changes in the processing of touch stimuli in the CNS, as previously thought. There is also growing evidence suggesting that peripheral mechanisms may contribute to some of the core symptoms and common comorbidities of ASD. Researchers are therefore beginning to assess the therapeutic potential of targeting the PNS in treating some of the core symptoms of ASD. Summary Sensory abnormalities are common in rodent models of ASD. There is growing evidence that sensory hypersensitivity, especially tactile sensitivity, may contribute to social deficits and other autism-related behaviors.

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Pleasurable touch during social behavior is the key to building familial bonds and meaningful connections. One form of social touch occurs during sex. Although sexual behavior is initiated in part by touch, and touch is ongoing throughout copulation, the identity and role of sensory neurons that transduce sexual touch remain completely unknown. A population of sensory neurons labeled by the G-protein coupled receptor Mrgprb4 detect stroking touch in mice. Here, we study the social relevance of this population by genetically engineering mice to allow activation or ablation of Mrgprb4-lineage neurons and reveal that these neurons are required for sexual receptivity and sufficient to activate reward circuitry. Even in social isolation, optogenetic stimulation of Mrgprb4-lineage neurons through the back skin is sufficient to induce a conditioned place preference and a striking lordosis-like copulatory posture in females. In the absence of Mrgprb4-lineage neurons, female mice no longer find male mounts rewarding: sexual receptivity is supplanted by aggression and a coincident decline in dopaminergic release in the mesolimbic reward pathway. In addition to sexual behavior, Mrgprb4-lineage neurons are also required for social postures induced by female-to-female back touch. Together, these findings reveal a skin-to-brain circuit encoding the rewarding quality of social touch.

Summary 23The chromatin remodeling gene CHD8 represents a central node in early neurodevelopmental 24 gene networks implicated in autism. We examined the impact of heterozygous germline Chd8 25 mutation on neurodevelopment in mice. Network analysis of neurodevelopmental gene 26 expression revealed subtle yet strongly significant widespread transcriptional changes in Chd8 +/-27 mice across autism-relevant networks from neurogenesis to synapse function. Chd8 +/-expression 28 signatures included enrichment of RNA processing genes and a Chd8-regulated module featuring 29 altered transcription of chromatin remodeling, splicing, and cell cycle genes. Chd8 +/-mice 30 exhibited increased proliferation during brain development and neonatal increase in cortical 31 length and volume. Structural MRI confirmed regional brain volume increase in adult Chd8 +/-32 mice, consistent with clinical macrocephaly. Adult Chd8 +/-mice displayed normal social 33 interactions, and repetitive behaviors were not evident. Our results show that Chd8 +/-mice 34 exhibit neurodevelopmental changes paralleling CHD8 +/-humans and show that Chd8 is a global 35 genomic regulator of pathways disrupted in neurodevelopmental disorders.

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