ACTIVITY DEPENDENT MECHANISMS NEURAL CIRCUIT FORMATION

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Neural circuitry underlies the fundamental functions of the nervous system. The development of neural circuitry is highly organized and precise. Abnormal neural development and improperly maintained neural connections lead to neurological and mental diseases, which are debilitating and devastating. To understand the mechanisms that underlie circuit formation is fundamental to our understanding of the pathology of neural diseases and may lead to discovery of proper cures. Yet with 10/12 neurons and 10/15 connections amongst them, the nervous system poses one of the most complex problems to study. Despite considerable progress in understanding fundamental aspects of neural development, knowledge of the cellular and molecular mechanisms in circuit development and maintenance are limited. The studies outlined here will investigate the role of intrinsic neural activity in the formation and maintenance of proper neuronal connections. In particular, the studies use the mouse olfactory system as a model system. Olfactory receptor neurons show remarkable precision in their projection patterns. Neurons expressing the same odorant receptor gene converge to two among approximately 2000 topograpically fixed glomeruli in the olfactory bulb. Such precise targeting by olfactory neurons is believed to be partly mediated by the odorant receptors, but the mechanism is unknown. By analogs with neurons may play an important role in setting up a precise olfactory map. The focus of this study is to block neural activity and examine the effect of neuronal silencing on circuit formation. To achieve this goal, genetic methods will be used to create transgenic mice that can be induced to express a potassium channel in a tissue and temporal specific fashion. The expression of this potassium channel will substantially dampen neural excitability and suppress electrical activity. The projection patterns of silenced neurons can be directly visualized through reporter gene activity, and the role of neural activity in pattern formation can be directly assessed.