Despite major progress in understanding the embryonic origin and migration of major classes of cortical GABAergic interneurons, how distinct interneuron types are deployed to cortical layers with appropriate density and are integrated into cortical circuits remains unexplored. The chandelier cells (ChCs) represent a bona fide interneuron type that specifically innervates pyramidal cells (PCs) at axon initial segment, the site of action potential initiation. Using state-of-the-art mouse genetic approaches, we have established a robust experiment system for studying the assembly of a stereotyped ChC-PC circuit module. We have previously discovered that ChC fate is specified from progenitors of the medial ganglionic eminence during late neurogenesis. Once specified through lineage and birth timing mechanisms, young ChCs appear endowed with cell-intrinsic programs that guide their migration to achieve distinct laminar settlement. Importantly, ChCs in mature cortex mediate directional inhibitory control between PC ensembles defined by projection targets. The developmental mechanisms to achieve such exquisite specificity is unknown. In this proposal, we examine the general hypothesis that activity-dependent ChC apoptosis contributes to sculpting the selective connectivity between ChCs and PCs in the visual cortex, where we aim to link development mechanisms to functional significance. Based on substantial evidence, our Overall Hypothesis is that ChC density and connection specificity at the border region between primary and secondary visual cortex (V1 and lateral V2) is regulated by contra- and ipsi-lateral callosal PC inputs (CALPC), which are coordinated by retinal activities; and reduced innervation of CALPCs by ChCs may facilitate bilateral communication that integrates Inter- hemispheric visual response properties. We will first characterize the development of ChC-PC connectivity at V1/V2 border region (Aim1). We will then determine how contralateral CALPC axons and activity regulate ChC density at the border (Aim2). We will further determine how retinal activities regulate ChC density at V1/V2 border (Aim3). Finally, we will examine the role of ChCs in regulating bilateral synchronization of visual response properties in the two visual hemispheres (Aim4). Our study will provide exceptional clarity in elucidating how genetic and activity dependent mechanisms coordinate to shape circuit wiring with cell type resolution in the mammalian brain. These studies will reveal novel activity-dependent mechanisms of neuronal pruning that shape highly specific circuit connectivity and may have implications in neurodevelopmental disorders such as autism spectrum disorders and schizophrenia.
Activity dependent integration of chandelier cells during cortical circuit assembly Narrative We will combine genetic, anatomical, physiological and imaging approaches to study how genetic instructions and neuronal activity orchestrate the developmental assembly of specific cell types into neural circuit in the cerebral cortex. These studies may shed light into our understanding of pathogenesis of neurodevelopmental disorders such as autism spectrum disorders and schizophrenia.
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