Mechanisms of Mammalian Neuronal Integration

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DESCRIPTION (provided by applicant): Understanding how individual neurons in the mammalian central nervous system (CNS) communicate with each other requires detailed knowledge of the factors that regulate both synaptic transmission and the processing of synaptic signals by postsynaptic neurons (synaptic integration). In this project, we will address these issues by capitalizing on some key technical advantages offered by specific giant synaptic connections and postsynaptic neurons in central auditory pathways. We will study the properties of the same synapses and neurons in both normal and congenitally deaf animals, to gain insight into the role of activity in the development and regulation of synaptic strength and postsynaptic membrane properties in central pathways. Synaptic transmission and postsynaptic integration are inextricably linked - our study offers an extremely valuable opportunity to investigate both phenomena as comprehensively as possible in the same central neurons. Our aims employ patch-clamp recording of synaptic and membrane currents from calyceal axon terminals and their postsynaptic neurons, in parallel with immunolabeling and electron microscopy to localize key synaptic and membrane proteins and determine synaptic structure, and with computational methods to help understand the roles of specific ion channels in synaptic integration. The aims will test the hypotheses that altered auditory system activity during development (1) leads to changes in synaptic strength, structure, ion channel expression and neuronal excitability, and (2) disrupts the normal tonotopic organization of auditory circuits. The proposed research will use detailed, multidisciplinary approaches to study synaptic structure, function, and integration in a region of the mammalian nervous system that is highly advantageous for this purpose. The combined skills and resources of two experienced and productive laboratories will be brought to bear on these fundamental issues, which heretofore have been difficult to address in the mammalian CNS. The organization and geometry of auditory neurons and synapses allows electrophysiological and immunohistochemical results to be directly compared. The results to be obtained will be of general significance for understanding mechanisms of synaptic transmission and integration, and of clinical significance in understanding the changes that occur in the central auditory system under conditions of chronic sensory deprivation.