title: Selective activation of α7 nicotinic acetylcholine receptors augments hippocampal oscillations.
abstract: 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.
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Stoiljkovic
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Kelley
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Dávid
authors.initials: D
authors.lastname: Nagy
authors.affiliation: FORUM Pharmaceuticals Inc., Waltham, MA, 02451, USA.
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. Electronic address: mihaly.hajos@yale.edu.
authors.forename: Mihály
authors.initials: M
authors.lastname: Hajós
mesh_terms: D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018722:Nicotinic Agonists / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D011812:Quinuclidines / Q000378:metabolism / Q000494:pharmacology; D013826:Theta Rhythm / Q000187:drug effects / Q000502:physiology*; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism*
chemical_list: C000604696:7-fluoro-N-quinuclidin-3-yl)benzo(b)thiophene-2-carboxamide; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D018722:Nicotinic Agonists; C498513:PNU-282987; D011812:Quinuclidines; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Hippocampus; Knock-out mice; Phase-amplitude coupling; Theta oscillation; α7 nAChR agonists