Nicotinic receptors (nAChRs) participate in moving muscles, making memories, and reinforcing our most fundamental behaviors. CNS nAChRs are implicated in normal cognitive functions, and their loss may underlie memory deficits associated with central cholinergic neurodegeneration. Stimulation of cholinergic projections or application of nicotine directly excites neurons by gating postsynaptic nAChRs and indirectly alters excitability by activating presynaptic nAChRs, thereby enhancing transmitter release. Despite the key role of nAChRs in synaptic """"""""tuning"""""""" and transmission, little is known of the regulatory mechanisms responsible for the expression, biophysical profile or cellular targeting of nAChRs in the CNS. This application examines the cellular and molecular mechanisms underlying the regulation of nAChR expression at specific CNS synapses. We first test whether interactions between pre- and postsynaptic partners control nAChRs expression and the maturation of cholinoceptive sites in the CNS. The role of synaptic interactions in the expression and targeting of nAChRs to presynaptic sites will be assayed in combined biophysical and molecular biological studies of nAChRs in visceral motor neurons and medial habenula neurons before and after synapse formation. Parallel studies of input-induced changes in postsynaptic nAChRs compare the expression profile and properties of nAChRs in interpeduncular and amygdala neurons before and after synaptogenesis. We next test the hypothesis that cysteine-rich-domain neuregulins (CRD-NRG) are required for the synaptic differentiation of cholinoceptive neurons in the CNS. Prior studies show that input-derived CRD-NRG controls nAChRs expression in chick PNS and that CRD-NRG and NRG receptors (erbBs) are expressed by cholinergic and cholinoceptive neurons in chick and mouse. To determine the role of CRD-NRG in mammalian synaptogenesis, we generated a CRD-NRG """"""""knock-out"""""""" mouse. Proposed experiments assess the expression of CRD-NRG, erbBs and nAChRs in developing cholinoreceptive neurons within medial habenula, interpeduncular and amygdala neurons. If CRD-NRG is required for the maturation of CNS cholinoceptive synapses, as it is in the periphery, we predict significant perturbations of the normal profile of expression and cellular targeting of nAChR channels to pre- and postsynaptic sites in CRD-NRG (-/-) mice. A final, long-range goal is to determine the signaling cascades activated by CRD-NRG. These studies pursue initial findings that both anterograde and retrograde signaling cascades are activated by CRD-NRG/erbB interactions.
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