Neurobiology of Aging 32 (2011) 614–623 Protection against A-mediated rapid disruption of synaptic plasticity and memory by memantine Igor Klyubin a,b,1 , Qinwen Wang c,d,1 , Miranda N. Reed e,f,1 , Elaine A. Irving g , Neil Upton g , Jacki Hofmeister i , James P. Cleary f,h,i,1 , Roger Anwyl b,c,1 , Michael J. Rowan a,b,∗,1 a Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland b Trinity College Institute of Neuroscience, Dublin 2, Ireland c Department of Physiology, Trinity College, Dublin 2, Ireland d Department of Physiology and Pharmacology, Medical School, Ningbo University, Ningbo, China e N. Bud Grossman Center, University of Minnesota, Minneapolis, MN, 55455, USA f Department of Neurology, University of Minnesota, Minneapolis, MN, 55455, USA g Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom h Department of Psychology, University of Minnesota, Minneapolis, MN, 55455, USA i Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Minneapolis, MN, 55417, USA Received 3 March 2009; received in revised form 30 March 2009; accepted 6 April 2009 Available online 14 May 2009 Abstract Soluble amyloid- protein (A) may cause cognitive impairment in Alzheimer’s disease in the absence of significant neurodegeneration. Here, the ability of the NMDA receptor (NMDAR) antagonist memantine to prevent synthetic A-mediated rapid functional deficits in learned behavior and synaptic plasticity was assessed in the rat. In vitro, pretreatment with a clinically relevant, NMDAR blocking concentration of memantine partially inhibited the induction of long-term potentiation (LTP) in the dentate gyrus and prevented further inhibition caused by exposure to A 1–42 . Whereas systemic injection with memantine alone inhibited LTP in the CA1 area in vivo, a subthreshold dose partially abrogated the inhibition of LTP by intracerebroventricular soluble A 1–42 . Similarly, systemic treatment with memantine alone impaired performance of an operant learning task and a subthreshold dose prevented the A 1–42 -mediated increase in perseveration errors. The acute protection afforded by memantine, albeit in a narrow dose range, against the rapid disruptive effects of soluble A 1–42 on synaptic plasticity and learned behavior strongly implicate NMDAR-dependent reversible dysfunction of synaptic mechanisms in A-mediated cognitive impairment. © 2009 Elsevier Inc. All rights reserved. Keywords: Amyloid- protein; Memantine; NMDA receptor; Long-term potentiation; Excitatory synaptic transmission; Learning; Memory; Alzheimer’s disease 1. Introduction Initial research on the involvement of amyloid- protein (A) in the dementia of Alzheimer’s disease laid particular emphasis on investigating the putative neurotoxicity of the fibrillar form of A, large quantities of which accumulate ∗ Corresponding author at: Department of Pharmacology and Therapeu- tics, Trinity College, Dublin 2, Ireland. Tel.: +353 18961567; fax: +353 18961466. E-mail address: mrowan@tcd.ie (M.J. Rowan). 1 These authors contributed equally to the work. as insoluble plaques in the brain as the disease progresses (Lorenzo and Yankner, 1996). Consistent with this hypothe- sis, pre-aggregated A containing fibrils can cause delayed cognitive effects that are associated with neurodegeneration (Maurice et al., 1996; McDonald et al., 1994; Nitta et al., 1994; Stephan et al., 2001). However, there is a poor correla- tion between the brain’s load of fibrillar A and cognitive sta- tus at the time of death for patients with clinical Alzheimer’s disease (Roth et al., 1966; Terry, 1996). A much stronger relationship exists between dementia severity and the concen- tration of soluble A species (Lue et al., 1999; McLean et al., 1999; Wang et al., 1999). Growing evidence strongly suggests 0197-4580/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2009.04.005