We propose to investigate the structure and function of synapses using a combination of molecular, biophysical, immunological and cell biological techniques. We focus on neuropeptides, receptors and cell surface molecules, and will investigate the roles that they play at synapses in the abdominal ganglion of Aplysia, the vertebrate retina, the mammalian neuromuscular junction and the mammalian CNS. The proposal builds on work in five different laboratories whose principal investigators have diverse technical backgrounds, but share a common interest in synaptic function and development. The group is united by our investigation of related problems in different systems, and by an emphasis on the use of immunological and molecular techniques in combination with both classical and modern physiological methods. We address three types of neural signaling systems: the classical excitatory synapse represented by the neuromuscular junction, in which there is a single presynaptic terminal and postsynaptic receptor; more complex synapses, such as those in the retina and mammalian CNS, in which there may be more than one postsynaptic receptor for a given transmitter; and more diffuse signalling systems as in the abdominal ganglion of Aplysia where a variety of peptides released by a single cell have diverse effects on many cells in the ganglion. To investigate how these systems function and develop, we will study the integrin receptors of nerve that mediate interactions with the extracellular matrix during neurite outgrowth, and the role of proteoglycans in pre- and postsynaptic differentiation. We will characterize the interaction between NMDA and non-NMDA receptors and the contribution of each to the excitatory postsynaptic response. We will isolate cDNAs for glutamate-sensitive channels and use antibodies to investigate their location in the CNS. We will also clone genes and cDNAs for physiologically active peptides in Aplysia; and finally, we will clone receptors for peptides and study their location and function.
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