NACHO Mediates Nicotinic Acetylcholine Receptor Function throughout the Brain

Neuronal nicotinic acetylcholine receptors (nAChRs) participate in diverse aspects of brain function and mediate behavioral and addictive properties of nicotine. Neuronal nAChRs derive from combinations of alpha and beta subunits, whose assembly is tightly regulated. NACHO was recently identified as a chaperone for alpha 7-type nAChRs. Here, we find NACHO mediates assembly of all major classes of presynaptic and postsynaptic nAChR tested. NACHO acts at early intracellular stages of nAChR subunit assembly and then synergizes with RIC-3 for receptor surface expression. NACHO knockout mice show profound deficits in binding sites for a-bungarotoxin, epibatidine, and conotoxin MII, illustrating essential roles for NACHO in proper assembly of alpha 7-, alpha 4 beta 2-, and alpha 6-containing nAChRs, respectively. By contrast, GABA(A) receptors are unaffected consistent with NACHO specifically modulating nAChRs. NACHO knockout mice show abnormalities in locomotor and cognitive behaviors compatible with nAChR deficiency and underscore the importance of this chaperone for physiology and disease associated with nAChRs.