Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 82, Issue 6, Pages 771-777Publisher
WILEY
DOI: 10.1002/jnr.20684
Keywords
mecamylamine; hippocampal slices; dentate gyrus; Alzheimer's disease
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Funding
- NIA NIH HHS [R03-AG022605] Funding Source: Medline
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Both impaired nicotinic neurotransmission and the inheritance of apoE4 are associated with increased risk for Alzheimer disease (AD) as well as other deficiencies in memory-related behavior. Long-term potentiation (LTP), a cellular model of memory, is known to be altered by nicotinic agents. Recent studies also support an emergent role for apoE in LTP. We compared the effects of mecamylamine, a nonspecific antagonist of nicotinic acetylcholine receptors (nAChRs), on basal synaptic transmission and LTP in hippocampal slices from wild-type (wt) mice and targeted replacement mice expressing human apoE4 (apoE4-TR). Field excitatory postsynaptic potentials (EPSPs) were recorded in the dentate gyrus (DG) in response to medial perforant path activation, and theta burst stimulation was used to induce LTR Bath application of mecamylamine (3 mu M) did not alter input-output relationships or paired pulse depression in either mouse strain. Under control conditions, apoE4-TR mice showed significantly less LTP than wt mice (17.5% +/- 3.2%, n = 9, vs. 30.1% +/- 3.9%, n = 11, P < 0.02). Mecamylamine reduced LTP in wt mice to a level that was similar to control levels for apoE4TR mice (15.7% +/- 3.4%, n = 9), whereas apoE4TR showed no further reduction of LTP (16.6% +/- 3.7%, n = 8) by mecamylamine. Thus mice expressing human apoE4 differ from wt mice both in their capacity for LTP and in the effect on LTP of nicotinic cholinergic blockade. It is possible that nicotinic neurotransmission is already compromised in apoE4-TR mice and, hence, that interference with the integrity of this cholinergic system represents a mechanism by which inheritance of the apoE4 allele contributes to cognitive risk. (c) 2005 Wiley-Liss, Inc.
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