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Roles of Mafb and c-Maf in MGE-derived cortical interneuron development and maturation

Abstract

An imbalance of excitation and inhibition in key neural circuits is hypothesized to underlie some epileptic disorders and neuropsychiatric diseases, such as schizophrenia and autism spectrum disorder (ASD) (Lim et al., 2018a; Rubenstein and Merzenich, 2003; Sohal and Rubenstein, 2019; Yizhar et al., 2011) . Inhibition in the cortex is primarily generated by cortical interneurons (CINs). CINs are produced by the medial and caudal ganglionic eminences (MGE and CGE). 70% of CINs are MGE-derived and primarily express Parvalbumin (PV+) or Somatostastin (SST+). CINs become postmitotic in the MGE, then tangentially migrate to the cortex, where they mature and integrate into local cortical circuits (Lim et al., 2018a). Great gaps remain in our understanding of the cellular and molecular mechanisms regulating CIN generation, migration and maturation.

My thesis work is to focus on elucidating the function of Mafb and c-Maf in MGE-lineage CIN development and maturation. Using conditional Maf knockout animal models together with immunohistochemistry, in vitro primary neuronal culture, in vivo MGE transplantation assay, electrophysiology and single-cell RNA-sequencing techniques, we profiled the expression pattern of Mafb and c-Maf (Chapter 2), and identified that Mafb and c-Maf function together prenatally in the MGE to control SST+ CIN neurogenesis (Chapter 3), while postnatally they function antagonistically in the CINs to control CIN synaptogenesis, morphogenesis and firing properties (Chapter 4). On-going pursuit is to try to figure out the molecular mechanism that is downstream of Mafb and c-Maf to lead to the phenotypes we have observed in the conditional mutants (Chapter 6).

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