Functional Studies of NDD Gene(s)

Project Summary/Abstract Neurodevelopmental disorders are common, debilitating disorders including autism, intellectual disability, and perhaps even schizophrenia. Recent genetic findings have identified mutations in multiple genes in various cellular pathways as genetic causes of rare neurodevelopmental disorders including autism spectrum disorders, intellectual disability, and others. This proposal will characterize a genetic mouse model, already generated and breeding in our laboratory, to delineate its function in the brain for the first time. Specifically, the proposal will be on a gene implicated in a well-defined neurodevelopmental disorder, as well as in autism and schizophrenia. Because this gene encodes a protein that is known to alter gene expression and chromatin modifications in non-neuronal cells, we will obtain multiome single nucleus RNA-sequencing and snATAC-seq data and analyze and correlate these two data sets while examining in parallel chromatin state. These data will span 3 critical time points during development and two key brain regions. We will also examine morphological changes in brain subregions using structural MRI as well as the morphology of neurons in the brain of these mice. A broad behavioral profile including learning/memory, social domain, and repetitive domains will be obtained to provide outcome measures for future studies. Finally, we will examine synaptic and neuronal function in two select brain regions using slice electrophysiology approaches. These unbiased, experiments will identify novel downstream targets in mammalian brain, elucidate behavioral outcome measures for future studies, and generate new hypotheses anticipated to lead to future potential therapeutic strategies.