Regulation of alpha7 nAChRs and NACHO

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Tsunoda, Susan Project Summary Nicotinic acetylcholine receptors (nAChRs) are involved in a wide range of physiological processes, from motor activity to complex brain functions, including learning/memory function and attention. nAChRs have also been shown to mediate homeostatic synaptic plasticity (HSP), a protective mechanism stabilizing neural activity. As such, dysfunction or loss of nAChRs has been implicated in a variety of neurological diseases. For example, the α7 nAChR has been implicated in Alzheimer’s Disease, nicotine addiction, nicotine-induced seizures, as well as schizophrenia. Indeed, enhancing nAChR signaling is a long-validated approach to treating multiple neuropsychiatric/pathological disorders. Despite this importance, much remains to be understood about how nAChRs are assembled and trafficked to the plasma membrane in neurons, especially when neurons encounter changes in activity. The proposed studies focus on NACHO, a newly identified endoplasmic reticulum (ER)- resident protein, shown to be a client-specific chaperone of nAChRs, and essential for trafficking α7 nAChRs. We use molecular-genetic approaches in Drosophila to overcome some of the limitations of studying intracellular α7 nAChRs in mammalian neurons. We: 1) examine the temporal relationship of NACHO and α7 nAChR up- regulation during HSP, 2) test whether NACHO and α7 depend on one another during HSP and whether one is sufficient to up-regulate the other, and 3) examine how the localization of α7 and NACHO in the ER/Gogli changes during HSP.