Functional α7ß2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid ß peptides.

BACKGROUND: ß-amyloid (Aß) accumulation is described as a hallmark of Alzheimer's disease (AD). Aß perturbs a number of synaptic components including nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs), which are abundantly expressed in the hippocampus and found on GABAergic interneurons. We have previously demonstrated the existence of a novel, heteromeric α7ß2-nAChR in basal forebrain cholinergic neurons that exhibits high sensitivity to acute Aß exposure. To extend our previous work, we evaluated the expression and pharmacology of α7ß2-nAChRs in hippocampal interneurons and their sensitivity to Aß. RESULTS: GABAergic interneurons in the CA1 subregion of the hippocampus expressed functional α7ß2-nAChRs, which were characterized by relatively slow whole-cell current kinetics, pharmacological sensitivity to dihydro-ß-erythroidine (DHßE), a nAChR ß2* subunit selective blocker, and α7 and ß2 subunit interaction using immunoprecipitation assay. In addition, α7ß2-nAChRs were sensitive to 1 nM oligomeric Aß. Similar effects were observed in identified hippocampal interneurons prepared from GFP-GAD mice. CONCLUSION: These findings suggest that Aß modulation of cholinergic signaling in hippocampal GABAergic interneurons via α7ß2-nAChRs could be an early and critical event in Aß-induced functional abnormalities of hippocampal function, which may be relevant to learning and memory deficits in AD.