Genetic analysis of chandelier cells during cortical circuit assembly

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DESCRIPTION (provided by applicant): In mammalian cerebral cortex, GABAergic inhibitory interneurons regulate the functional organization of neural circuitry. Inhibitory interneurons consist of diverse classes with distinct morphology, connectivity patterns, and physiological properties. The stereotypy and specificity in cortical interneurons suggest stringent genetic programs in their construction and assembly. Understanding the development of GABA interneurons is necessary to gaining a coherent knowledge on the assembly cortical circuits. Although much progress has made in understanding the early development of cortical interneurons, from their generation in the ventral telencephalon to their long distance migration into the cortex, it is still unclear how distinct classes of interneuron are specified and delivered to appropriate cortical areas and layers. Furthermore, little is known about how interneurons are integrated into cortical circuitry. A key obstacle is the lack of method and strategy that allow the developmental history of any well-defined class of interneurons to be tracked from their origin to their integration into cortical circuits. We have undertaken a systematic genetic approach to target major classes of cortical interneurons. In particular, we have genetically captured chandelier cells (CHCs), the most distinctive class of cortical interneurons that exclusively innervate pyramidal cells at axon initial segments, the site of action potential generation. CHCs are thus likely the most powerful cortical neurons that exert decisive control over pyramidal cell firing, thereby dynamically configure neural ensembles. However, current knowledge on CHCs is poor, and their origin and development are almost entirely unknown. Because of their exceptional stereotypy and specificity, genetic capture of CHCs establishes a powerful experimental paradigm for studying their entire developmental history. We will examine three developmental milestones of CHCs: origin, settlement into specific cortical lamina, and massive pruning during circuit integration. Using genetic engineering, fate mapping, in vivo imaging, and electrophysiology, we will achieve a high resolution description of these key events, and begin to explore the underlying molecular mechanisms. We aim to establish a cell type-based experimental paradigm that will longitudinally integrate key developmental steps in the larger context of making and integrating CHCs into cortical circuits. Deficiencies in CHCs have been implicated in several brain disorders such as epilepsy and schizophrenia. Genetic analysis of CHCs not only will provide a key entry point to understanding the assembly of neocortical circuitry but also will shed light into the pathogenic mechanisms of neuropsychiatric disorders and suggest new strategies for therapy.