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The Journal of Neuroscience, January 28, 2009, 29(4):918-929; doi:10.1523/JNEUROSCI.3952-08.2009

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Neurobiology of Disease
A Novel Nicotinic Acetylcholine Receptor Subtype in Basal Forebrain Cholinergic Neurons with High Sensitivity to Amyloid Peptides

Qiang Liu,¹ Yao Huang,³ Fenqin Xue,² Alain Simard,² Jamie DeChon,¹ Guohui Li,¹ Jianliang Zhang,² Linda Lucero,² Min Wang,⁴ Michael Sierks,⁴ Gang Hu,⁵ Yongchang Chang,² Ronald J. Lukas,² and Jie Wu¹

Divisions of ¹Neurology and ²Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013-4496, ³Department of Obstetrics and Gynecology, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85004, ⁴Department of Chemical Engineering, Arizona State University, Tempe, Arizona 85281, and ⁵Department of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China

Correspondence should be addressed to Dr. Jie Wu, Division of Neurology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013-4496. Email: jie.wu{at}chw.edu

Nicotinic acetylcholine receptors (nAChRs) containing 7 subunits are thought to assemble as homomers. 7-nAChR function has been implicated in learning and memory, and alterations of 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, 7 subunits are coexpressed, colocalize, and coassemble with β2 subunit(s). Compared with homomeric 7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric 7β2-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 β2 subunit-containing nAChR-selective antagonist, dihydro-β-erythroidine (DHβE). Interestingly, presumed, heteromeric 7β2-nAChRs are highly sensitive to functional inhibition by pathologically relevant concentrations of oligomeric, but not monomeric or fibrillar, forms of amyloid β_1–42 (Aβ_1–42). Slow whole-cell current kinetics, sensitivity to DHβE, and specific antagonism by oligomeric Aβ_1–42 also are characteristics of heteromeric 7β2-nAChRs, but not of homomeric 7-nAChRs, heterologously expressed in Xenopus oocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to Aβ when elicited from MS/DB neurons derived from nAChR β2 subunit knock-out mice rather than from wild-type mice. The presence of novel, functional, heteromeric 7β2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric Aβ_1–42 suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies.

Key words: nicotinic receptor; basal forebrain; cholinergic neurons; patch clamp; amyloid β; Alzheimer's disease

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Received Aug. 19, 2008; revised Dec. 2, 2008; accepted Dec. 16, 2008.

Correspondence should be addressed to Dr. Jie Wu, Division of Neurology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013-4496. Email: jie.wu{at}chw.edu

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