TY - JOUR
T1 - Implications of oligomeric amyloid-beta (oAβ42) signaling through α7β2-nicotinic acetylcholine receptors (nAChRs) on basal forebrain cholinergic neuronal intrinsic excitability and cognitive decline
AU - George, Andrew A.
AU - Vieira, Jaime M.
AU - Xavier-Jackson, Cameron
AU - Gee, Michael T.
AU - Cirrito, John R.
AU - Bimonte-Nelson, Heather A.
AU - Picciotto, Marina R.
AU - Lukas, Ronald J.
AU - Whiteaker, Paul
N1 - Funding Information: This work was primarily supported by Arizona Biomedical Research Commission ADHS14-083003 to A.A.G., Arizona Alzheimer’s Consortium to A.A.G., and Barrow Neurological Foundation endowment and capitalization funds to A.A.G. This work was also supported by the National Institutes of Health R21 AG067029 to A.A.G. and R01 DA 043567 to A.A.G. and P.W. and R01 DA042749 to P.W. We thank Jason A. Miranda and Dale J. Buskirk for critical feedback on the manuscript; and Linda M. Lucero for technical assistance with concatemer design and construction. The authors declare no competing financial interests. Correspondence should be addressed to Andrew A. George at Andrew.George@dignityhealth.org. https://doi.org/10.1523/JNEUROSCI.0876-20.2020 Copyright © 2021 the authors Publisher Copyright: Copyright © 2021 the authors.
PY - 2021/1/20
Y1 - 2021/1/20
N2 - Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-β (Aβ) 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-β (oAβ42), interacting with α7-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 oAβ42 activates both homomeric α7- and heteromeric α7β2-nAChR subtypes while preferentially enhancing α 7β2- 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 oAβ42 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 β2 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 α 7β2-nAChR in mediating the effects of oAβ42 on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of α7β2-nAChR in oAβ42 -induced cognitive decline.
AB - Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-β (Aβ) 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-β (oAβ42), interacting with α7-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 oAβ42 activates both homomeric α7- and heteromeric α7β2-nAChR subtypes while preferentially enhancing α 7β2- 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 oAβ42 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 β2 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 α 7β2-nAChR in mediating the effects of oAβ42 on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of α7β2-nAChR in oAβ42 -induced cognitive decline.
KW - Basal forebrain cholinergic neurons
KW - Medium afterhyperpolarization
KW - Neuronal intrinsic excitability
KW - Oligomeric amyloid-beta
KW - Single-channel electrophysiology
KW - Spatial reference memory
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U2 - https://doi.org/10.1523/JNEUROSCI.0876-20.2020
DO - https://doi.org/10.1523/JNEUROSCI.0876-20.2020
M3 - Article
C2 - 33239400
SN - 0270-6474
VL - 41
SP - 555
EP - 575
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 3
ER -