A Novel Nicotinic Acetylcholine Receptor Subtype In Basal Forebrain Cholinergic Neurons With High Sensitivity To Amyloid Peptides
Nicotinic acetylcholine receptors (nAChRs) containing Î±7 subunits are thought to assemble as homomers. Î±7-nAChR function has been implicated in learning and memory, and alterations of Î±7-nAChR have been found in patients with Alzheimer's disease (AD). Here we report findings consistent with a novel, naturally occurring nAChR subtype in rodent, basal forebrain cholinergic neurons. In these cells, Î±7 subunits are coexpressed, colocalize, and coassemble with Î²2 subunit(s). Compared with homomeric Î±7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric Î±7Î²;2-nAChRs on cholinergic neurons freshly dissociated from medial septum/diagonal band (MS/DB) exhibit relatively slow kinetics of whole-cell current responses to nicotinic agonists and are more sensitive to the Î²;2 subunit-containing nAChR-selective antagonist, dihydro-Î²- erythroidine (DHÎ²E). Interestingly, presumed, heteromeric Î±7Î²2-nAChRs are highly sensitive to functional inhibition by pathologically relevant concentrations of oligomeric, but not monomeric or fibrillar, forms of amyloid Î²1-42 (AÎ²1-42). Slow whole-cell current kinetics, sensitivity to DHÎ²E, and specific antagonism by oligomeric AÎ²1-42 also are characteristics of heteromeric Î±7Î²2-nAChRs, but not of homomeric Î±7-nAChRs, heterologously expressed in Xenopus oocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to AÎ² when elicited from MS/DB neurons derived from nAChR Î²2 subunit knock-out mice rather than from wild-type mice. The presence of novel, functional, heteromeric Î±7Î²2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric AÎ²1-42 suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies. Copyright Â© 2009 Society for Neuroscience.
Journal of Neuroscience
Digital Object Identifier (DOI)
Liu, Qiang; Huang, Yao; Xue, Fenqin; Simard, Alain; DeChon, Jamie; Li, Guohui; Zhang, Jianliang; Lucero, Linda; Wang, Min; Sierks, Michael; Hu, Gang; Chang, Yongchang; Lukas, Ronald J.; and Wu, Jie, "A Novel Nicotinic Acetylcholine Receptor Subtype In Basal Forebrain Cholinergic Neurons With High Sensitivity To Amyloid Peptides" (2009). Neurobiology. 181.