Nicotinic acetylcholine receptors (nAChRs) function at key interneuronal and central sensory organ synapses. Their activation mediates excitatory transmission, reinforces nicotine addiction, increases memory formation, and regulates the sensitivity of hearing. Malfunction of cholinergic synapses has been implicated in developmental and neurodegenerative disorders such as Alzheimer's disease, schizophrenia, nocturnal frontal lobe epilepsy, and autoimmune autonomic neuropathies. Despite the physiological importance of nicotinic synapses, little is known about the molecular mechanisms that direct their assembly during development. Further, proper synapse formation and function require precise alignment of pre- and postsynaptic specializations, but the underlying mechanisms are poorly understood. Our recent studies identify adenomatous polyposis coli (APC) as a key molecular player in interneuronal cholinergic synapse assembly in vivo. We show that APC is essential for localizing a3-nAChRs to postsynaptic sites, and thereby identify APC as the first non-receptor protein to function in nAChR targeting to neuronal synapses. We propose that APC has two key synapse organizing functions: (1) directing nAChR transport to and/or stabilization at postsynaptic sites (Aim1) and (2) directing the alignment of pre- and postsynaptic specializations by anchoring retrograde signaling complexes at sites of nAChR accumulation (Aim2). Further, we posit that APC'S interactions with three essential postsynaptic components: microtubule plus end binding protein-1 (EB1), beta-catenin and postsynaptic density protein-93 (PSD-93) mediate these essential aspects of synapse formation. We will use loss-of-function and gain-of-function strategies to test the specific roles of these APC interactions and binding partners in organizing cholinergic synapses in vivo. We will test APC'S role at two different nicotinic preparations: a3-nAChR-containing peripheral ciliary ganglion neuronal synapses and a9-nAChR-containing central efferent olivocochlear synapses on sensory hair cells of the inner ear. The experiments will use genetic, molecular, morphological, biochemical and functional approaches. The studies will provide important new insights into molecular interactions that direct the assembly and function of cholinergic synapses. Further, the studies will determine whether the organizational mechanisms are shared between peripheral neuron and central sensory nicotinic synapses.
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