Blockade of nicotinic acetylcholine receptors suppresses hippocampal long-term potentiation in wild-type but not ApoE4 targeted replacement mice.
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 LTP. Bath application of mecamylamine (3 microM) 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 apoE4-TR mice (15.7% +/- 3.4%, n = 9), whereas apoE4-TR 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.
Yun
Sung Hwan
SH
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Park
Kyung A
KA
Sullivan
Patrick
P
Pasternak
Joseph F
JF
Ladu
Mary Jo
MJ
Trommer
Barbara L
BL
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D013997:Time Factors
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D008464:Mecamylamine