Molecular Mechanisms of Somatostatin Interneuron Diversity

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PROJECT SUMMARY The multitude and complexity of cortical functions is shaped by the diversity of cortical interneurons populations. Specifically, somatostatin interneuron, which comprise one-third of all cortical interneurons, route the flow of information within the cortex by targeting and selectively inhibiting the dendrites of excitatory pyramidal neurons. Recent efforts have demonstrated that cortical somatostatin interneurons are themselves further divided into various subtypes. Many studies have characterized the distinct and heterogenous properties of somatostatin interneuron subtypes in the functioning adult brain and their diverse contributions to cortical function, but the mechanisms by which this diversity is generated during development are relatively unknown. Recent studies have devoted considerable effort into obtaining a descriptive account of interneuron diversification during development by profiling the transcriptomic and epigenetic events that unfold during cortical interneuron development, but these studies also fall short of presenting a mechanistic explanation. Our lab and others have previously demonstrated the requirement of the transcription factor Satb1 for the proper development of cortical somatostatin interneurons. Interestingly, removal of Satb1 has heterogeneous effects within the somatostatin interneuron population, suggesting that it may contribute to the generation of diverse features within the somatostatin interneuron population. Moreover, single-cell transcriptomic sequencing data shows that Satb1 is expressed at varying levels across distinct somatostatin interneuron subtypes. Thus, In this proposal, I present the hypothesis that Satb1, in a concentration-dependent manner, contributes to somatostatin interneuron diversity during development by controlling distinct genetic programs. I will test this hypothesis using a combination of intersectional mouse genetics, epigenetic and transcriptomic profiling, and microscopy. In Aim 1 I seek to characterize varying Satb1 protein levels across somatostatin interneuron subtypes and the phenotype of Satb1 removal. In Aim 2 I seek to understand the mechanism by which varying Satb1 levels may lead to distinct genetic programs. Successful completion of this study will help to elucidate fundamental mechanisms by which the brain creates neuronal diversity during development. Furthermore, these studies will highlight new exciting principles for gene regulation. These data along with the research and scientific expertise developed through this Kirschstein-NRSA F30 Fellowship Award will support my long-term goal of becoming an independent investigator.