Functional α7β2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid β peptides

Background: beta-amyloid (A beta) accumulation is described as a hallmark of Alzheimer's disease (AD). A beta perturbs a number of synaptic components including nicotinic acetylcholine receptors containing alpha 7 subunits (alpha 7-nAChRs), which are abundantly expressed in the hippocampus and found on GABAergic interneurons. We have previously demonstrated the existence of a novel, heteromeric alpha 7 beta 2-nAChR in basal forebrain cholinergic neurons that exhibits high sensitivity to acute A beta exposure. To extend our previous work, we evaluated the expression and pharmacology of alpha 7 beta 2-nAChRs in hippocampal interneurons and their sensitivity to A beta. Results: GABAergic interneurons in the CA1 subregion of the hippocampus expressed functional alpha 7 beta 2-nAChRs, which were characterized by relatively slow whole-cell current kinetics, pharmacological sensitivity to dihydro-beta-erythroidine (DH beta E), a nAChR beta 2* subunit selective blocker, and alpha 7 and beta 2 subunit interaction using immunoprecipitation assay. In addition, alpha 7 beta 2-nAChRs were sensitive to 1 nM oligomeric A beta. Similar effects were observed in identified hippocampal interneurons prepared from GFP-GAD mice. Conclusion: These findings suggest that A beta modulation of cholinergic signaling in hippocampal GABAergic interneurons via alpha 7 beta 2-nAChRs could be an early and critical event in A beta-induced functional abnormalities of hippocampal function, which may be relevant to learning and memory deficits in AD.