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The Journal of Neuroscience, July 1, 2001, 21(13):4691-4698

Age-Related Impairment of Synaptic Transmission But Normal Long-Term Potentiation in Transgenic Mice that Overexpress the Human APP695SWE Mutant Form of Amyloid Precursor Protein

Stephen M. Fitzjohn¹, Robin A. Morton^{1, 2, 3}, Frederick Kuenzi^{1, 3}, Thomas W. Rosahl³, Mark Shearman³, Huw Lewis³, David Smith³, David S. Reynolds³, Ceri H. Davies², Graham L. Collingridge¹, and Guy R. Seabrook³

¹ Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol, BS8 1TD, United Kingdom, ² Department of Pharmacology, University of Edinburgh, Edinburgh, EH8 9JZ, United Kingdom, and ³ Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex, CM20 2QR, United Kingdom

We have studied synaptic function in a transgenic mouse strain relevant to Alzheimer's disease (AD), overexpressing the 695 amino acid isoform of human amyloid precursor protein with K670N and M671L mutations (APP₆₉₅SWE mice), which is associated with early-onset familial AD. Aged-transgenic mice had substantially elevated levels of A (up to 22 µmol/gm) and displayed characteristic A plaques. Hippocampal slices from 12-month-old APP₆₉₅SWE transgenic animals displayed reduced levels of synaptic transmission in the CA1 region when compared with wild-type littermate controls. Inclusion of the ionotropic glutamate receptor antagonist kynurenate during preparation of brain slices abolished this deficit. At 18 months of age, a selective deficit in basal synaptic transmission was observed in the CA1 region despite treatment with kynurenate. Paired-pulse facilitation and long-term potentiation (LTP) were normal in APP₆₉₅SWE transgenic mice at both 12 and 18 months of age. Thus, although aged APP₆₉₅SWE transgenic mice have greatly elevated levels of A protein, increased numbers of plaques, and reduced basal synaptic transmission, LTP can still be induced and expressed normally. We conclude that increased susceptibility to excitotoxicity rather than a specific effect on LTP is the primary cause of cognitive deficits in APP₆₉₅SWE mice.

Key words: Alzheimer's disease; synaptic plasticity; LTP; hippocampus; APP; transgenic

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21134691-08$05.00/0

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