The goal of this proposal is to continue the characterization of fundamental and distinctive features of GABA receptor function and inhibitory mechanisms in the mammalian CNS. Alterations in GABAA receptor-mediated inhibition take place over the course of several neurological and psychiatric disorders, and numerous clinically used drugs including anxiolytics, anesthetics and anticonvulsants have GABAA receptor-dependent mechanisms of action. In light of this, the proposed studies will contribute to the understanding of inhibition and its alterations by neuronal activity, drugs or disease states. The proposal will characterize two distinct forms of GABAergic activity in central neurons: phasic inhibition mediated by activation of GABAA receptors at synapse, and tonic inhibition that is most likely generated by extrasynaptic receptors activated by ambient GABA present in the extracellular space. The central hypothesis to be tested is as follows: tonic and phasic GABAergic inhibition are separately generated and differently regulated in the central nervous system. Consequently, the two inhibitions perform distinct functions to control the excitability of individual neurons and of interconnected neuronal networks.
Each specific aim addresses critical features of the two types of inhibition.
These aims are: 1) to establish the differential pharmacology of the two types of inhibition; 2) to study their regulation by endogenous factors; 3) to resolve how the two inhibitions control the activity of interneurons; 4) to identify distinct subclasses of interneurons explicitly involved in producing one or the other type of inhibition; 5) to uncover the role played by the two types of inhibition in regulating the excitability of neuronal networks. To establish these goals, high resolution electrophysiological recordings will be obtained from neurons identified with IR-DIC and fluorescent methods. Light and electron microscopical investigations will address the specific anatomical properties and localization of the receptors and cells involved. Moreover, the study will use genetically altered mice that over- or under-express certain GABA receptors in specific neuronal populations. Other mutant mice have well-defined subclasses of interneuron expressing specific markers to facilitate their identification for electrophysiological recordings or for their specific photochemical ablation by exposure to UV light. The study is expected to yield novel and specific insights into the functioning of the GABAergic system in the brain. Understanding the role and the specific control of the two types of inhibition will lead to a better grasp of many clinical problems associated with alterations in inhibitory function including those underlying cognitive processes. A thorough knowledge of the regulation of GABAergic inhibition by endogenous factors and by specific drugs will open the possibility for novel therapies aimed at curing some devastating psychiatric and neurological disorders including anxiety, stress, stroke, and epilepsy.
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