Mechanisms underlying basal and learning-related intrinsic excitability in a mouse model of Alzheimer's disease.
Accumulations of β-amyloid (Aβ) contribute to neurological deficits associated with Alzheimer's disease (AD). The effects of Aβ 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 Aβ42 (and elevated levels of Aβ38-40) in naïve 5XFAD mice was associated with decreased basal neuronal excitability, evidenced by a select increase in Ca(2+)-sensitive afterhyperpolarization (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 naïve 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 Aβ and disrupt basal excitability via a Ca(2+)-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).
Kaczorowski
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CC
Northwestern University Interdepartmental Neuroscience Program, Chicago, IL 60611, USA. ckaczorowski@mcw.edu
Sametsky
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Shah
S
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Vassar
R
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Disterhoft
J F
JF
D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D053764:Presenilin-1 / Q000235:genetics* / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D002118:Calcium