| First Author | George AA | Year | 2021 |
| Journal | J Neurosci | Volume | 41 |
| Issue | 3 | Pages | 555-575 |
| PubMed ID | 33239400 | Mgi Jnum | J:300750 |
| Mgi Id | MGI:6502691 | Doi | 10.1523/JNEUROSCI.0876-20.2020 |
| Citation | George AA, et al. (2021) Implications of Oligomeric Amyloid-Beta (oAbeta42) Signaling through alpha7beta2-Nicotinic Acetylcholine Receptors (nAChRs) on Basal Forebrain Cholinergic Neuronal Intrinsic Excitability and Cognitive Decline. J Neurosci 41(3):555-575 |
| abstractText | Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-beta (Abeta) and contribute to cognitive deficits associated with Alzheimer's disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study, we tested the hypothesis that the oligomeric form of amyloid-beta (oAbeta42), interacting with alpha7-containing nicotinic acetylcholine receptor (nAChR) subtypes, leads to subnucleus-specific alterations in BFCN excitability and impaired cognition. We used single-channel electrophysiology to show that oAbeta42 activates both homomeric alpha7- and heteromeric alpha7beta2-nAChR subtypes while preferentially enhancing alpha7beta2-nAChR open-dwell times. Organotypic slice cultures were prepared from male and female ChAT-EGFP mice, and current-clamp recordings obtained from BFCNs chronically exposed to pathophysiologically relevant level of oAbeta42 showed enhanced neuronal intrinsic excitability and action potential firing rates. These resulted from a reduction in action potential afterhyperpolarization and alterations in the maximal rates of voltage change during spike depolarization and repolarization. These effects were observed in BFCNs from the medial septum diagonal band and horizontal diagonal band, but not the nucleus basalis. Last, aged male and female APP/PS1 transgenic mice, genetically null for the beta2 nAChR subunit gene, showed improved spatial reference memory compared with APP/PS1 aged-matched littermates. Combined, these data provide a molecular mechanism supporting a role for alpha7beta2-nAChR in mediating the effects of oAbeta42 on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of alpha7beta2-nAChR in oAbeta42-induced cognitive decline. |
