Altered GluN2B NMDA receptor function and synaptic plasticity during early pathology in the PS2APP mouse model of Alzheimer's disease

• Type of Material: Article
• Authors: Jesse E. Hanson, Genentech Inc.; Jean-Francois Pare, Emory University; Lunbin Deng, Genentech Inc.; Yoland Smith, Emory University; Qiang Zhou, Genentech Inc.
• Language: English
• Date: 2015-02-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2014 Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.nbd.2014.11.017
• Title of Journal or Parent Work: Neurobiology of Disease
• ISSN: 0969-9961
• Volume: 74
• Start Page: 254
• End Page: 262
• Grant/Funding Information: YS and J-FP received financial support from the NIH base grant to the Yerkes Primate Center (RR00165).
• Keywords: Alzheimer's disease; NMDA receptor; AMYLOID DEPOSITION; SUBUNIT IMMUNOREACTIVITY; D-ASPARTATE RECEPTOR; POTENTIATION; NR2B; TRANSGENIC MICE; LTD; ACTIVATION; Ro25-6981; Neurosciences; Perisynaptic; Neurosciences & Neurology; LTP; OLIGOMERS; LOCALIZATION; Life Sciences & Biomedicine; METABOTROPIC GLUTAMATE RECEPTORS; Science & Technology; PS2APP; LONG-TERM DEPRESSION; GluN2B; Synaptic plasticity
• Research Categories: Biology, Neuroscience

Abstract

GluN2B subunit containing NMDARs (GluN2B-NMDARs) mediate pathophysiological effects of acutely applied amyloid beta (Aβ), including impaired long-term potentiation (LTP). However, in transgenic Alzheimer's disease (AD) mouse models which feature gradual Aβ accumulation, the function of GluN2B-NMDARs and their contribution to synaptic plasticity are unknown. Therefore, we examined the role of GluN2B-NMDARs in synaptic function and plasticity in the hippocampus of PS2APP transgenic mice. Although LTP induced by theta burst stimulation (TBS) was normal in PS2APP mice, it was significantly reduced by the selective GluN2B-NMDAR antagonist Ro25-6981 (Ro25) in PS2APP mice, but not wild type (wt) mice. While NMDARs activated by single synaptic stimuli were not blocked by Ro25, NMDARs recruited during burst stimulation showed larger blockade by Ro25 in PS2APP mice. Thus, the unusual dependence of LTP on GluN2B-NMDARs in PS2APP mice suggests that non-synaptic GluN2B-NMDARs are activated by glutamate that spills out of synaptic cleft during the burst stimulation used to induce LTP. While long-term depression (LTD) was normal in PS2APP mice, and Ro25 had no impact on LTD in wt mice, Ro25 impaired LTD in PS2APP mice, again demonstrating aberrant GluN2B-NMDAR function during plasticity. Together these results demonstrate altered GluN2B-NMDAR function in a model of early AD pathology that has implications for the therapeutic targeting of NMDARs in AD.