Title: P3-055: Progressive age-related impairment of the late long-term potentiation in Alzheimer's disease presenilin-1 mutant knock-in mice
Abstract: Presenilin 1 (PS1) mutations are responsible for many early-onset familial Alzheimer'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 early phase of LTP (E-LTP). Among PS1 mouse models, PS1 M146V knock-in mice (PS1KI) are particularly interesting in that they exhibit impairment in spatial tasks (Sun et al, 2005). Here we investigated the effects of aging on two forms of LTP in PS1KI mice, the widely studied 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. Recording are from the cA1 region of hippocampal slices. Baseline fEPSPs was recorded during 30 min and L-LTP was recorded during 4 hours. E-LTP and L-LTP were recorded from PS1KI and wild-type littermate control at the age of 3, 6, 9, and 12 months. All mice were maintained on an homogenous genetic background (C57BL/6). At 3 month of age, we observed a larger L-LTP induction from than PS1KI than from WT littermates during the first 30 min of recording. PS1KI mice exhibited a decrease in L-LTP amintenance. At the same age, we observed an increase in the E-LTP in PS1KI mice compared to WT mice. From 6 month of age to 12 month the L-LTP was impaired thoughout the 4 hours of recording compred to WT. E-LTP were still increased in 6 month old PS1KI compared to WT littermates. At 9 months of age, no significant difference was found between E-LTP of PS1KI and WT littermates. At 12 months of age, E-LTP was significantly decreased compare to WT littermates. We identify an early impairment of L-LTP maintenance which may explained the impairment in spatial memory induced by PS1 (M146V) KI mutation. The E-LTP is increased at an early stage, but decline at middle age (12 months).