Aβ-induced epileptiform activity disrupts learning and enhances forgetting in transgenic models of Alzheimer’s disease
South Hall A
Tuesday, Oct 20, 2009, 11:00 AM -12:00 PM
, M. THWIN, K. HO, L. MUCKE, *J. J. PALOP;
Gladstone Instit and UCSF, San Francisco, CA
Alzheimer’s disease (AD) is associated with high levels of amyloid-β peptide (Aβ), increased incidence of seizures, and progressive cognitive decline. We previously demonstrated that high Aβ levels trigger generalized epileptic activity and intense remodeling of hippocampal circuits in a mouse model of AD (hAPPJ20). However, causal relations between Aβ-induced epileptic activity, remodeling of hippocampal circuits, and cognitive decline have not yet been established. To test whether epileptic activity critically contributes to hippocampal remodeling and cognitive impairments in transgenic mouse models of AD, we pharmacologically manipulated Aβ-induced epileptiform activity in hAPPJ20 mice and evaluated the effect of such manipulation on hippocampal remodeling and cognitive decline. Chronic exacerbation of Aβ-induced electroencephalographic (EEG) epileptic activity enhanced hippocampal remodeling, including NPY/GABAergic sprouting in the molecular layer, ectopic expression of NPY in the mossy fibers, and depletions of calbindin in the granule cells, suggesting that Aβ-induced remodeling of hippocampal circuits is indeed a downstream effect of aberrant excitatory neuronal activity. Importantly, increasing Aβ-induced epileptic activity disrupted acquisition of new memories (learning), which relies heavily on hippocampal functions, but also retrieval of consolidated memories (remembering), which appears to involve neocortical functions. We conclude that aberrant excitatory neuronal activity represents an early step in the pathogenic cascade leading from Aβ to cognitive deficits in transgenic mouse models of AD and possibly also in humans with AD.
Supported by the Stephen D. Bechtel Jr. Foundation and the NIH.
Stephen D. Bechtel Jr. Foundation and the NIH.
[Authors]. [Abstract Title]. Program No. XXX.XX. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online.
2009 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
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