In late embryogenesis, the auditory nerve forms synaptic contacts on bushy neurons, producing what will become some of the most highly specialized synapses in the brain. During this early period of development, these terminals generate a cadre of morphological specializations and selective expression of key neurotransmitter receptors that are absolutely essential to auditory processing in the adult. How does this happen? In this proposal, we focus on a striking event in the developmental of the relay: many of the initial synaptic contacts utilize the NMDA receptor for transmission, but over a period of just days these synapses or their receptors are nearly completely removed. NMDA receptors, which are receptors for the transmitter glutamate, are well known to mediate or regulate a variety of cellular processes in development and in adults, due primarily to their unusual voltage dependence and their ability to cause increases in the second messenger Ca 2+. Yet, because of their slow channel kinetics, they are poorly suited to the relay function of these synapses. Rather, these receptors could play a major role in formation of auditory synapses and circuits. We will examine several aspects of the function of these receptors in young chick cochlear nucleus and test hypotheses related to their mechanisms of removal. In particular, we will monitor the formation of a unique subpopulation of synapse that almost exclusively utilizes the NMDA receptor and determine the location of these synapses on the dendritic tree. We intend to find out how these receptors contribute to electrical responses believed to occur in embryos, since much evidence suggests this activity is also an important determinative factor in auditory function. Possible mechanisms for removal of supernumerary synaptic contacts in development will be tested, which may require the NMDA receptor. Finally we will conduct experiments in which the function of NMDA receptors are blocked in vivo, and assay how this manipulation alters the course of development. The results of this study should reveal how expression and regulation of a major transmitter receptor guides formation of an important neuronal element of the auditory system and provide clues as to the functional significance of auditory nerve activity in young animals prior to the onset of hearing. ? ?

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Freeman, Nancy
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Oregon Health and Science University
Schools of Medicine
United States
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