Hippocampal network dynamics in response to alpha 7 nACh receptors activation in amyloid-beta overproducing transgenic mice

摘要

Amyloid-beta (A beta) peptide overproduction is one of the pathomechanisms contributing to Alzheimer's disease (AD). Agonists of alpha 7 nicotinic acetylcholine receptors (alpha 7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that alpha 7 nAChR agonists may improve cognitive functions in AD patients. However, interactions between A beta and alpha 7 nAChRs have been observed, implying that high levels of A beta may modify the effects of alpha 7 nAChR agonists. Therefore, we tested the alpha 7 nAChR agonist FRM-17874, an analogue of encenicline, in 8-month-old A beta 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. (C) 2016 Elsevier Inc. All rights reserved.