Selective activation of α7 nicotinic acetylcholine receptors augments hippocampal oscillations

Neural alpha 7 nicotinic acetylcholine receptors (alpha 7 nAChRs) emerged as a potential pharmacologic target for treating cognitive deficits in schizophrenia and Alzheimer's disease. Experiments modeling these dysfunctions, as well as clinical evidence, demonstrate the relatively consistent procognitive effects of alpha 7 nAChR agonists. One preclinical observation supporting the procognitive role of alpha 7 nAChRs is their ability to modulate neuronal network oscillations closely associated with learning and memory, especially hippocampal oscillations. Due to the high degree of structural similarity between alpha 7 nACh and 5-HT receptors, the majority of alpha 7 nAChR agonists to date also act as 5-HT3 antagonists. To address this confounding property and determine the relevance of alpha 7 nAChR agonist binding to 5-HT3 receptors in modulating hippocampal activity, we tested two well-described alpha 7 nAChR agonists, PNU-282987 and FRM-17874, in mice lacking alpha 7 nAChRs (alpha 7 knock-out, alpha 7KO) using the brainstem simulation-elicited hippocampal theta oscillation assay. Under urethane anesthesia both agonists at equivalent doses demonstrated efficacy in wild-type (WT) mice, significantly enhancing theta power and theta phase gamma amplitude coupling as compared to saline treated control mice. These effects are comparable to those seen with drugs clinically used to treat Alzheimer's disease. Although alpha 7KO mice showed no alterations in elicited hippocampal oscillations, both alpha 7 nAChR agonists failed to enhance theta power or theta phase - gamma amplitude coupling in these mice. Our findings demonstrate that selective activation of alpha 7 nAChRs can modulate hippocampal oscillation, and these receptors are the primary targets of the tested agonists, PNU-282987 and FRM-17874 and likely underlies their observed procognitive activity. (C) 2016 Elsevier Ltd. All rights reserved.