title: Chronic GluN2B antagonism disrupts behavior in wild-type mice without protecting against synapse loss or memory impairment in Alzheimer's disease mouse models.
abstract: Extensive evidence implicates GluN2B-containing NMDA receptors (GluN2B-NMDARs) in excitotoxic-insult-induced neurodegeneration and amyloid β (Aβ)-induced synaptic dysfunction. Therefore, inhibiting GluN2B-NMDARs would appear to be a potential therapeutic strategy to provide neuroprotection and improve cognitive function in Alzheimer's disease (AD). However, there are no reports of long-term in vivo treatment of AD mouse models with GluN2B antagonists. We used piperidine18 (Pip18), a potent and selective GluN2B-NMDAR antagonist with favorable pharmacokinetic properties, for long-term dosing in AD mouse models. Reduced freezing behavior in Tg2576 mice during fear conditioning was partially reversed after subchronic (17 d) Pip18 treatment. However, analysis of freezing behavior in different contexts indicated that this increased freezing likely involves elevated anxiety or excessive memory generalization in both nontransgenic (NTG) and Tg2576 mice. In PS2APP mice chronically fed with medicated food containing Pip18 for 4 months, spatial learning and memory deficits were not rescued, plaque-associated spine loss was not affected, and synaptic function was not altered. At the same time, altered open field activity consistent with increased anxiety and degraded performance in an active avoidance task were observed in NTG after chronic treatment. These results indicate that long-term treatment with a GluN2B-NMDAR antagonist does not provide a disease-modifying benefit and could cause cognitive liabilities rather than symptomatic benefit in AD mouse models. Therefore, these results challenge the expectation of the therapeutic potential for GluN2B-NMDAR antagonists in AD.
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Hanson
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080.
authors.forename: William J
authors.initials: WJ
authors.lastname: Meilandt
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080.
authors.forename: Alvin
authors.initials: A
authors.lastname: Gogineni
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080.
authors.forename: Paul
authors.initials: P
authors.lastname: Reynen
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080.
authors.forename: James
authors.initials: J
authors.lastname: Herrington
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080.
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.affiliation: Department of Neuroscience, Genentech, South San Francisco, California 94080 zhouqiang@PKUSZ.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000139:chemically induced*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008569:Memory Disorders / Q000209:etiology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D013569:Synapses / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010880:Piperidines; C032727:piperidine
keywords: Alzheimer's disease; GluN2B; NMDAR; cognition; memory; spine