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'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.

Figure 1

Induction of L-LTP, E-LTP, and NMDA-R mediated transmission are increased by mutant PS1, while the maintenance phase of L-LTP is decreased at 3 months of age. A) At 3 months, the L-LTP protocol induced a significantly larger induction in PS1KI mice than in +/+ mice during the first 30 min of recording (p<0.05). No significant differences were observed between PS1KI and +/+ mice for the interval from 30 min to 3 h after HFS. However, during the interval from 3 to 4 h the PS1KI mice exhibited a significant decrease in L-LTP which returned progressively to the baseline, compared to +/+ mice (p<0.001). * corresponds to p<0.05. fEPSPs traces of baseline and post-LTP recordings are represented. B) At 3 months, the E-LTP protocol induced a significantly larger response in PS1KI mice than in +/+ littermates (p<0.001). * corresponds to p<0.05. fEPSPs traces of baseline and post-LTP recordings are represented. C) Paired-Pulse Facilitation (PPF) was unchanged at 3 months of age. D) At 3 months, analysis of Input-Output (I-O) slopes demonstrates a significant increase of NMDA receptor mediated responses in PS1KI mice compared +/+ littermates (p<0.05). * corresponds to p<0.05. E) No significant difference was found between the two groups of mice at any stimulus level examined for averaged I-O plots of AMPA receptor mediated responses.

Figure 2

Induction and maintenance phases of L-LTP are decreased while E-LTP is increased by mutant PS1 at 6 months of age. A) At 6 months, the L-LTP protocol induced a significantly lower induction and maintenance in PS1KI mice than in +/+ mice during the 4 h of recording (p<0.001). * corresponds to p<0.05. B) At 6 months, the E-LTP protocol induced a significantly larger response in PS1KI mice than in +/+ littermates (p<0.05). However, E-LTP levels in PS1KI at 6 months were lower than E-LTP levels in PS1KI at 3 months of age (p<0.05). * corresponds to p<0.05. C) PPF was unchanged at 6 months of age. D) At 6 months, NMDA receptor mediated responses did not differ between the two groups. E) No significant difference was found between the two groups of mice at any stimulus level examined for averaged Input-Output plots of AMPA receptor mediated responses.

Figure 3

Induction and maintenance phases of L-LTP are decreased while E-LTP is unchanged by mutant PS1 at 9 months of age. A) At 9 months, the L-LTP protocol induced a significantly lower induction and maintenance in PS1KI mice than in +/+ mice during the 4 h of recording (p<0.001). * corresponds to p<0.05. (B) At 9 months, E-LTP analysis revealed no significant differences between the two groups. C) PPF was unchanged at 9 months of age. D) NMDA receptor mediated responses were unchanged at 9 months of age between the two groups. E) No significant difference was found between the two groups of mice at any stimulus level examined for averaged Input-Output plots of AMPA receptor mediated responses.

Figure 4

Induction and maintenance phases of L-LTP, E-LTP, and NMDA-R mediated transmission are decreased by mutant PS1 at 12 months of age. A) At 12 months, the L-LTP protocol induced a significantly lower induction and maintenance in PS1KI mice than in +/+ mice during the 4 h of recording (p<0.001). * corresponds to p<0.05. B) At 12 months, E-LTP analysis revealed a significant decrease in PS1KI mice compared +/+ littermates (p<0.05). * corresponds to p<0.05. C) PPF was unchanged at 12 months of age. D) At 12 months, analysis of Input-Output slopes demonstrates a significant decrease of basal NMDA receptor-dependant synaptic transmission in PS1KI mice compared to WT mice (p<0.05). * corresponds to p<0.05. E) No significant difference was found between the two groups of mice at any stimulus level examined for averaged Input-Output plots of AMPA receptor mediated responses.

Figure 5

Means of normalized fEPSP slopes for different periods of L-LTP at 3, 6, 9, and 12 months of age. A) For the recording interval 0h00-0h30, L-LTP is significantly increased in PS1KI mice compared to +/+ mice at 3 months of age (p<0.05). By contrast, at 6, 9 and 12 months of age, L-LTP is significantly decreased in PS1KI mice (p<0.001). * corresponds to p<0.05. B) For the recording interval from 60–90 min after HFS, L-LTP is similar between PS1KI mice and +/+ mice at 3 months of age. By contrast, at 6, 9 and 12 months, L-LTP is significantly decreased in PS1KI mice compared to +/+ littermates (p<0.001). * corresponds to p<0.05. C) Recordings made between 2.5 and 3 h after LTP induction reveal that L-LTP is similar between PS1KI mice and +/+ mice at 3 months of age. By contrast, at 6, 9 and 12 months of age, L-LTP was markedly altered in PS1KI mice compared to +/+ littermates (p<0.001). * corresponds to p<0.05. D) Recordings made between 3.5 and 4 h after HFS showed that, at all ages L-LTP is significantly decreased in PS1KI mice compared to +/+ littermates (p<0.001). * corresponds to p<0.05.