PROJECT SUMMARY Neurodevelopmental disorders (NDD) are a group of highly prevalent conditions that affects 1-10% of children in the United States. These disorders are highly heterogenous and present with a wide range of cognitive, social, and behavioral deficits. One of the most commonly mutated genes in NDD is ARID1B, which encodes a subunit of the BRG1/BRM-Associated Factor (BAF) chromatin remodeling complex. BAF complexes establish regions of accessible chromatin at non-coding cis-regulatory elements (cREs) in the genome, which initates gene transcription. ARID1B is one of the most enriched genes for de novo mutations in NDD patients, and ARID1B mutations cause NDDs with a variety of phenotypic manifestations. However, it is not well understood how de novo coding mutations in ARID1B impact the gene regulatory networks during neuronal development that lead to NDDs. While de novo mutations in ARID1B lead to NDDs, many NDD patients do not present with a coding mutation in ARID1B. Genomic studies have shown an excess of de novo mutations in putative cREs in NDD cohorts, implicating non-coding mutations in the pathogenesis of these disorders. While there is a strong indication of mutations in cREs in NDDs, the location of cREs that direct the translation of ARID1B are not known, nor looked at for de novo mutations that can cause NDDs. To bridge these gaps in knowledge, I will investigate the impact of coding and non-coding mutations in ARID1B on neuronal development. To this end, I will characterize Arid1b halpoinsufficient mice at the single-cell level that are known to exhibit behavioral and morphological deficits reminiscent of those seen in NDD patients. This will allow me to identify patterns of dysregulation to chromatin accessibility and gene expression at multiple timepoints of development. I will also identify putative enhancer regions of ARID1B using chromatin interaction and single-cell(sc) co-accessibility datasets. With these data I will be able to characterize enhancers that regulate ARID1B expression. Moreso, with these data I will identify an enrichment of de novo mutations in enhancers of ARID1B that lead to NDDs. This work will provide a better understanding of how mutations in coding and non-coding regions of ARID1B and dysregulate critical molecular mechanisms necessary for normal neuronal development during embryogenesis that leads to NDDs.