Selective activation of α7 nicotinic acetylcholine receptors augments hippocampal oscillations

- α7 nAChRs activation improves cognition making them potential targets for treating Alzheimer's disease and schizophrenia.
- The majority of α7 nAChR agonists also act as 5-HT3 antagonists due to high structural homology between the receptors.
- Contribution of off-target binding was measured for two α7 nAChR agonists in induced hippocampal oscillations in α7KO mice.
- The effects of α7 nAChR agonists PNU-282987 and FRM-17874 are absent in α7KO mice.
- The effects of α7 nAChR agonists in enhancing hippocampal oscillations is exclusively mediated via α7 nAChRs.

Neural α7 nicotinic acetylcholine receptors (α7 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 α7 nAChR agonists. One preclinical observation supporting the procognitive role of α7 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 α7 nACh and 5-HT receptors, the majority of α7 nAChR agonists to date also act as 5-HT3 antagonists. To address this confounding property and determine the relevance of α7 nAChR agonist binding to 5-HT3 receptors in modulating hippocampal activity, we tested two well-described α7 nAChR agonists, PNU-282987 and FRM-17874, in mice lacking α7 nAChRs (α7 knock-out, α7KO) 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 α7KO mice showed no alterations in elicited hippocampal oscillations, both α7 nAChR agonists failed to enhance theta power or theta phase - gamma amplitude coupling in these mice. Our findings demonstrate that selective activation of α7 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.