Mechanisms underlying basal and learning-related intrinsic excitability in a mouse model of Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:32

Article

Kaczorowski, C. C.^1,2  Sametsky, E.²  Shah, S.²  Vassar, R.³  Disterhoft, J. F.² 

[1] Northwestern Univ, Interdept Neruosci Program, Chicago, IL 60611 USA

[2] Northwestern Univ, Dept Physiol M211, Feinberg Sch Med, Chicago, IL 60611 USA

[3] Northwestern Univ, Dept Cell & Mol Biol M211, Feinberg Sch Med, Chicago, IL 60611 USA

关键词: Hippocampus;    Afterhyperpolarization;    Fear conditioning;    Alzheimer's disease;    Trace fear conditioning;    CA1;    AHP;    Intrinsic excitability;    Intrinsic plasticity;    Aging;    AD;   

DOI  :  10.1016/j.neurobiolaging.2009.09.003

来源: Elsevier

【 摘 要 】

Accumulations of beta-amyloid (A beta) contribute to neurological deficits associated with Alzheimer's disease (AD). The effects of A beta on basal neuronal excitability and learning-related AHP plasticity were examined using whole-cell recordings from hippocampal neurons in the 5XFAD mouse model of AD. A robust increase in A beta 42 (and elevated levels of A beta 38-40) in naive 5XFAD mice was associated with decreased basal neuronal excitability, evidenced by a select increase in Ca2+-sensitive after hyperpolarization (AHP). Moreover, trace fear deficits observed in a subset of 5XFAD weak-learner mice were associated with a greater enhancement of the AHP in neurons, as compared to age-matched 5XFAD learner and 5XFAD naive mice. Importantly, learning-related plasticity of the AHP remained intact in a subset of 5XFAD mice that learned trace fear conditioning to a set criterion. We show that APP-PS1 mutations enhance A beta and disrupt basal excitability via a Ca2+-dependent enhancement of the AHP, and suggest disruption to learning-related modulation of intrinsic excitability resulted, in part, from altered cholinergic modulation of the AHP in the 5XFAD mouse model of AD (170 of 170). (C) 2009 Elsevier Inc. All rights reserved.

【 授权许可】

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