Affiliations: [a] Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche (UMR) 7102-Neurobiologie des Processus Adaptatifs (NPA); Centre National de la Recherche Scientifique (CNRS), UMR 7102-NPA, Paris, France | [b] Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD, USA | [c] Assistance Publique–Hôpitaux de Paris Hôpital Charles Foix, Unité d'Explorations Fonctionnelles, Ivry sur Seine, France
Correspondence:
[*]
Correspondence to: Alexandra Auffret, Université Pierre et Marie Curie, UMR 7102-Neurobiologie des Processus Adaptatifs (NPA); 9 quai St Bernard, case 14; 75005 Paris, France. Tel.: +33 1 44 27 32 43; Fax: +33 1 44 27 22 80; E-mail: alexandra.auffret@gmail.com.
Abstract: Presenilin 1 (PS1) mutations are responsible for many early-onset familial Alzheimer's disease (FAD) cases. While increasing evidence points to impaired synaptic plasticity as an early event in AD, PS1 mutant mice exhibit a paradoxical increase in hippocampal long-term potentiation (LTP). Among PS1 mouse models, PS1 M146V mutant knock-in mice (PS1KI) are particularly interesting in that they exhibit memory impairment in spatial tasks. Here we investigated the effects of aging on two forms of LTP in PS1KI mice, the widely-studied early phase of LTP (E-LTP) and a particular form of LTP called late-LTP (L-LTP) which requires transcription and protein synthesis. L-LTP is thought to be critical for long-term memory. We found a lower L-LTP maintenance phase in PS1KI mice compared to wild type littermates at 3 months of age. As the mice age, they exhibit impairment of both the induction and maintenance phases of LTP. When E-LTP and NMDA receptor-mediated transmission were analyzed, PS1KI mice displayed an increase at 3 months compared to wild type littermates; this difference did not persist at older ages and finally decreased at 12 months. These results reveal an L-LTP decrease in PS1 mutant mice at an early stage, which occurs coincidently with a paradoxical enhancement of E-LTP. The observation of a decrease in both forms of LTP during aging supports the view that PS1KI mice are a valuable model for the study of age-dependent synaptic dysfunction and cognitive decline in AD.
