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The Journal of Neuroscience, August 12, 2009, 29(32):10144-10152; doi:10.1523/JNEUROSCI.1856-09.2009

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Neurobiology of Disease
Age-Dependent Impairment of Spine Morphology and Synaptic Plasticity in Hippocampal CA1 Neurons of a Presenilin 1 Transgenic Mouse Model of Alzheimer's Disease

Alexandra Auffret,¹ Vanessa Gautheron,¹ Mariaelena Repici,¹ Rudolf Kraftsik,² Howard T. J. Mount,³ Jean Mariani,^1,4 and Catherine Rovira¹

¹Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche (UMR) 7102-Neurobiologie des Processus Adaptatifs (NPA), Centre National de la Recherche Scientifique, UMR 7102-NPA, Paris F-75005, France, ²Department of Cell Biology and Morphology, University of Lausanne, 1005 Lausanne, Switzerland, ³Department of Medicine, Division of Neurology, Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, Canada, and ⁴Assistance Publique–Hôpitaux de Paris Hôpital Charles Foix, Unité d'Explorations Fonctionnelles, Ivry sur Seine F-94200, France

Correspondence should be addressed to Alexandra Auffret, Université Pierre et Marie Curie, UMR 7102-Neurobiologie des Processus Adaptatifs, 9 quai St Bernard, case 14, Paris F-75005, France. Email: alexandraauffret{at}gmail.com

Presenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production of Aβ peptides. However, emerging evidence suggests other possible effects of PS1 on synaptic dysfunction where PS1 might contribute to the pathology independent of Aβ. We chose to study the L286V mutation, an aggressive FAD mutation which has never been analyzed at the electrophysiological and morphological levels. In addition, we analyzed for the first time the long term effects of wild-type human PS1 overexpression. We investigated the consequences of the overexpression of either wild-type human PS1 (hPS1) or the L286V mutated PS1 variant (mutPS1) on synaptic functions by analyzing synaptic plasticity and associated spine density changes from 3 to 15 months of age. We found that mutPS1 induces a transient increase observed only in 4- to 5-month-old mutPS1 animals in NMDA receptor (NMDA-R)-mediated responses and LTP compared with hPS1 mice and nontransgenic littermates. The increase in synaptic functions is concomitant with an increase in spine density. With increasing age, however, we found that the overexpression of human wild-type PS1 progressively decreased NMDA-R-mediated synaptic transmission and LTP, without neurodegeneration. These results identify for the first time a transient increase in synaptic function associated with L286V mutated PS1 variant in an age-dependent manner. In addition, they support the view that the PS1 overexpression promotes synaptic dysfunction in an Aβ-independent manner and underline the crucial role of PS1 during both normal and pathological aging.

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Received April 19, 2009; revised June 28, 2009; accepted July 7, 2009.

Correspondence should be addressed to Alexandra Auffret, Université Pierre et Marie Curie, UMR 7102-Neurobiologie des Processus Adaptatifs, 9 quai St Bernard, case 14, Paris F-75005, France. Email: alexandraauffret{at}gmail.com

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