Developmental cerebellar deficits caused by Chd8 haploinsufficiency

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SUMMARY The role of the cerebellum (CB) in proprioception and fine motor control is well-established, however more recent studies also strongly implicate this structure in higher order cognitive functions such as language, cognitive processing and affective regulation. Despite the tight relationship between these cerebellar functions and Neurodevelopmental Disorders (NDDs) such as Autism Spectrum Disorder (ASD) and Intellectual Disability (ID), the role of non-motor contributions of the CB is often overlooked in NDD research and especially understudied in animal models of these disorders compared to structures such as the cerebral cortex and hippocampus. With the emerging understanding that the CB plays a critical role in higher order brain function and that perturbed cerebellar functioning can lead to ASD and NDD relevant phenotypes, there is strong justification for focus on CB dysfunction in NDD animal models. De novo mutations in the chromatin- remodeling factor CHD8 (Chromodomain-Helicase DNA-binding protein 8) have emerged as a key genetic causal factor strongly associated with ASD and more generally with NDDs. Individuals harboring de novo heterozygous mutations in CHD8 typically present with hallmarks of ASD, cognitive disability, and macrocephaly, with other phenotypes also present in some patients. Multiple mouse Chd8 models have been published (including by our group), with heterozygous mutants exhibiting relevant phenotypes including macrocephaly and behavioral deficits. To date, animal models of pathology associated with CHD8 mutation have focused on the forebrain, and in particular the cerebral cortex. In published and preliminary studies, we identified altered structure of the deep cerebellar nuclei and evidence of altered cerebellar anatomy and physiology in mice harboring heterozygous Chd8 mutation. We hypothesize that cerebellar impact of Chd8 mutation contributes to higher order cognitive and behavioral pathology. Here, we propose initial work towards testing this model, defining the impact of Chd8 haploinsufficiency on cerebellar structure and function across anatomical, genomic, and electrophysiological dimensions. In Aim 1, we will test CB sensitivity to Chd8 haploinsufficiency with regard to patterning and cell identity. In Aim 2, we will test for phenotypes at the electrophysiological, transcriptomic and morphologic level in cerebellar neurons. These experiments will establish impacts of heterozygous Chd8 mutation on the mouse CB, linking neuroanatomy, neuronal function, and signaling. These studies will provide critical evidence for future work defining specific phenotypes associated with heterozygous Chd8 ablation in the CB and towards building a circuit level understanding of how Chd8 mutations impact connectivity within the CB and between the CB and other structures. If successful, this work will lead to new avenues of research on cerebellar dysfunction in NDDs and ASD by linking a high confidence and top priority gene with cellular, molecular, and structural deficits in the CB.