title: Altered GluN2B NMDA receptor function and synaptic plasticity during early pathology in the PS2APP mouse model of Alzheimer's disease.
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.
authors.affiliation: Genentech Inc., Department of Neuroscience, 1 DNA Way, MS 230B, South San Francisco, CA 94080, USA. Electronic address: hanson.jesse@gene.com.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Hanson
authors.affiliation: Yerkes National Primate Research Center, Department of Neurology, UDALL Center of Excellence for Parkinson's Disease, Emory University, 954, Gatewood Rd NE, Atlanta, GA, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pare
authors.affiliation: Genentech Inc., Department of Neuroscience, 1 DNA Way, MS 230B, South San Francisco, CA 94080, USA.
authors.forename: Lunbin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Yerkes National Primate Research Center, Department of Neurology, UDALL Center of Excellence for Parkinson's Disease, Emory University, 954, Gatewood Rd NE, Atlanta, GA, USA.
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.affiliation: Genentech Inc., Department of Neuroscience, 1 DNA Way, MS 230B, South San Francisco, CA 94080, USA. Electronic address: zhouqiang@PKUSZ.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology* / Q000648:ultrastructure; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981
keywords: Alzheimer's disease; GluN2B; LTD; LTP; NMDA receptor; NR2B; PS2APP; Perisynaptic; Ro25-6981; Synaptic plasticity