Nicotinic acetylcholine receptors (nAChRs) are widely expressed in the nervous system and have been implicated in a variety of behaviors and neuropathologies;In most cases the receptors reach their highest levels during late embryogenesis and early postnatal life. Almost nothing is known, however, about the developmental roles of neuronal nAChRs, other than that they are cation-selective and can regulate calcium- dependent events. We have preliminary evidence that during development nAChRs utilize signal transduction to regulate synaptic capabilities, including that of adjacent non-cholinergic pathways, in both the CNS and autonomic nervous systems. This proposal will test specific hypotheses about the roles of nicotinic input in shaping the development of nicotinic and GABAergic signaling, and will examine candidate molecules that may facilitate or transduce nicotinic effects.
In Aim I the chick ciliary ganglion is used to test hypotheses about the significance of newly discovered GABAergic pathways in this cholinergic ganglion, the role of nicotinic input in controlling GABAergic maturation from excitatory to inhibitory mode, and the consequences this has for ganglionic throughput.
In Aims II and III, the mammalian hippocampus is used to test hypotheses about the role of nicotinic signaling in regulating filopodia fate, induction of dendritic spines, maturation of GABAergic signaling from excitatory to inhibitory, and acute modulation of GABA responses. Long-lasting nicotine sensitization is also examined.
In Aims I V and V three candidate proteins that appear to specifically interact with neuronal nAChRs are examined for their roles in determining the number, location, function, and downstream signaling capabilities of the receptors. Each of these aims is based on preliminary data supporting the central hypotheses being tested. The experimental approaches include electrophysiology, imaging, molecular biology, and biochemistry, and are carried out on neurons in cell culture and slice preparations from wildtype and mutant sources. Together these approaches and systems should provide mechanistic insight into novel roles of nicotinic signaling in the developing nervous system. The findings should also have biomedical relevance in revealing the consequences of nicotine exposure during these formative periods.
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