Clonal Analysis of Neocortical Interneuron Circuit Development

Sloan-Kettering Inst Can Research, New York NY

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Abstract

DESCRIPTION (provided by applicant): Virtually all neuronal circuits in the mammalian neocortex are composed of glutamatergic excitatory neurons and GABAergic inhibitory interneurons. While excitatory neurons are responsible for generating the output, interneurons provide a rich variety of inhibitions through an extraordinary diversity in subtypes that often determine output. Extensive studies over the past decade have revealed key insights into the production and organization of excitatory neurons in the neocortex. In contrast, our knowledge of interneuron production and organization in the neocortex remains very limited. For example, it is unclear whether a single interneuron progenitor cell gives rise to different subtypes of interneurons and whether sister interneurons originating from the same progenitor cell are specifically organized and thereby provide potential anatomical substrates for the formation of functional circuits in the neocortex. To address these fundamental questions, we propose to perform clonal analysis of interneuron production, migration and structural and functional organization in the neocortex. To achieve our goals, we will develop innovative methods for effectively and selectively labeling interneuron progenitor cells in the ventral telencephalon - the ganglionic eminences - at clonal density. We will analyze the production, migration, and structural and functional organization of individual interneuron clones being labeled using state-of-the-art imaging (e.g. two photon lasers scanning microscopy) and electrophysiology (e.g. multi-electrode whole-cell patch clamp recording) approaches and link these processes to functional circuit formation in the neocortex. Interneuron malformation and dysfunction have been associated with many neurological and psychological disorders, such as epilepsy, schizophrenia and autism. Therefore, our research will not only provide fundamental insights into interneuron development and greatly advance our understanding of the functional organization of the neocortex, but will also shed light on the etiology of many devastating brain disorders. 1 PUBLIC HEALTH RELEVANCE: Interneurons are vital components of neural networks in the brain and are responsible for providing a rich variety of inhibition actions that restrain the brain activity. Malformation and dysfunction of interneruons have been linked to many neurological and psychological illnesses, including epilepsy, schizophrenia and autism. Our studies on interneuron production and organization in the mammalian brain will shed light on the etiology and thereby provide new ideas for the medical treatment of many of these devastating brain disorders. 1