title: Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice.
abstract: Amyloid-β (Aβ) peptide overproduction is one of the pathomechanisms contributing to Alzheimer's disease (AD). Agonists of α7 nicotinic acetylcholine receptors (α7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that α7 nAChR agonists may improve cognitive functions in AD patients. However, interactions between Aβ and α7 nAChRs have been observed, implying that high levels of Aβ may modify the effects of α7 nAChR agonists. Therefore, we tested the α7 nAChR agonist FRM-17874, an analogue of encenicline, in 8-month-old Aβ overproducing 5xFAD mice in an in vivo neurophysiological assay with a high construct and predictive validity for testing procognitive drugs. By recording changes in brainstem-stimulation-elicited hippocampal oscillations, we identified previously undescribed neurophysiological impairments in 5xFAD mice, including significantly decreased power of theta and gamma oscillations and theta-phase-gamma-amplitude coupling. Compared with their saline controls, systemically administered FRM-17874 significantly increased stimulation-induced theta power by 30% in both 5xFAD and wild-type mice. However, FRM-17874 did not impact gamma oscillation or theta-phase-gamma-amplitude coupling in either wild type or 5xFAD mice, and it did not eliminate the significant differences in these parameters between the 2 groups.
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 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, 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, USA.
authors.forename: Gábor Patrick
authors.initials: GP
authors.lastname: Hajós
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dávid
authors.initials: D
authors.lastname: Nagy
authors.affiliation: FORUM Pharmaceuticals Inc, Waltham, MA, USA.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Koenig
authors.affiliation: FORUM Pharmaceuticals Inc, Waltham, MA, 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, USA. Electronic address: mihaly.hajos@yale.edu.
authors.forename: Mihály
authors.initials: M
authors.lastname: Hajós
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D003071:Cognition; D005260:Female; D065818:Gamma Rhythm; D006624:Hippocampus / Q000502:physiology*; D008297:Male; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009415:Nerve Net / Q000502:physiology*; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013826:Theta Rhythm; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000378:metabolism*
chemical_list: C000604696:7-fluoro-N-quinuclidin-3-yl)benzo(b)thiophene-2-carboxamide; D016229:Amyloid beta-Peptides; D011812:Quinuclidines; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: 5xFAD mice; Alzheimer's disease; Hippocampal oscillations; Theta-gamma coupling; α7 nAChR agonist