Epigenetic regulators ASH1L and SETBP1 in GABAergic neuron development and ASD

Many ASD risk genes encode proteins involved in the gamma-aminobutyric acid (GABA)ergic system, regulating the development of GABAergic neurons, their functions, and the balance of excitation and inhibition in the brain. In the forebrain, GABAergic neurons are inhibitory neurons originating in a germinal zone of the embryonic basal ganglia, called the GE, from where they migrate to their final destinations throughout the forebrain. Within the cerebral cortex, these neurons function primarily as locally projecting interneurons (INs). Conversely, GABAergic projection neurons (PNs) predominantly populate subcortical regions such as the striatum, globus pallidus, and amygdalar complex. They contribute to motivated behavior, reward learning, and decision-making and there is evidence linking PNs to the etiology of ASD. Functional genomic approaches have significantly improved the identification of genetic susceptibility factors for ASD, providing a crucial starting point for studying causal disease mechanisms. Preliminary experiments have identified ASH1L and SETBP1, two HMTs previously established as high-risk candidates for ASD, as candidates for regulating differentiation and fate determination of GABAergic neurons through their interaction with enhancers that control lineage-specific gene expression and through epigenetic modifications. The investigators will introduce genetic perturbations at specific time points in embryonic development in mouse models to determine how inhibitory circuits are disturbed in autism.