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. 2009 Feb;33(2):229-35.
doi: 10.1016/j.nbd.2008.10.006. Epub 2008 Nov 5.

Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model

Ryoichi Kimura  1 , Masuo Ohno
Affiliations

Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model

Ryoichi Kimura et al. Neurobiol Dis. 2009 Feb.

Abstract

Although animal models of Alzheimer's disease (AD) recapitulate beta-amyloid-dependent hippocampal synaptic and cognitive dysfunctions, it is poorly understood how cortex-dependent remote memory stabilization following initial hippocampal coding is affected. Here, we systematically analyzed biophysical and behavioral phenotypes, including remote memory functions, of 5XFAD APP/PS1 transgenic mice containing five familial AD mutations. We found that 5XFAD mice show hippocampal dysfunctions as observed by reduced levels of baseline transmission and long-term potentiation at Schaffer collateral-CA1 synapses. Hippocampus-dependent memory tested 1 day after contextual fear conditioning was also impaired age-dependently in 5XFAD mice, as correlated with the onset of hippocampal synaptic failures. Importantly, remote memory stabilization during 30 days after training significantly declined in 5XFAD mice at time well before the onset of hippocampal dysfunctions. Our results indicate that 5XFAD mice provide a useful model system to investigate the mechanisms and therapeutic interventions for multiple synaptic and memory dysfunctions associated with AD.

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Figures

Fig. 1
Fig. 1
Age-dependent impairments of basal synaptic transmission in hippocampal slices from 5XFAD mice. A and B, Input/output (I/O) curves relating the amplitude of the presynaptic fiber volley to the slope of fEPSP at various stimulus intensities (20–100 μA) in the CA1 region of 5XFAD mice at <4 months (A) and 6 months (B) of ages. C, The summary bar graph shows significant reductions in basal synaptic transmission as measured by the average slope of I/O curves in 5XFAD mice at 6 months of age but not at <4 months of age (n = 9–11 mice per group). * P<0.05 versus wild-type controls. All data are presented as mean ± SEM.
Fig. 2
Fig. 2
Age-dependent impairments of LTP but not paired-pulse facilitation in hippocampal slices from 5XFAD mice. A and B, Paired-pulse facilitation across different inter-stimulus intervals (20–500 ms) is normal in the CA1 region of 5XFAD mice at <4 months (A) and 6 months (B) of ages (n = 6–12 mice per group). C–F, LTP induced by 10-TBS (C: <4 months of age, D: 6 months of age) and 3-TBS (E: <4 months of age, F: 6 months of age) in the CA1 region of 5XFAD mice. Each point indicates the fEPSP slope normalized to the average baseline response before TBS applied at time 0. Traces are the average of fEPSPs recorded during baseline and 30–40 min after TBS. Calibration: 0.1 mV, 10 ms. G and H, The summary bar graphs show significant reductions in LTP as measured by the average normalized fEPSP slopes during 30–40 min after TBS in 5XFAD mice at 6 months of age (H) but not at <4 months of age (G) (n = 5–8 mice per group). * P<0.05 versus wild-type controls. All data are presented as mean ± SEM.
Fig. 3
Fig. 3
Age-dependent impairments of contextual fear conditioning in 5XFAD mice. A and B, 5XFAD mice at <4 months (A) or 6 months (B) of age and their wild-type littermate mice were trained with a single CS-US pairing for contextual fear conditioning. 5XFAD mice at 6 months of age but not at <4 months of age show significantly lower levels of contextual freezing than wild-type mice when tested 1 day after training (n = 13–30 mice per group). * P<0.05 versus wild-type controls. All data are presented as mean ± SEM.
Fig. 4
Fig. 4
Normal memory extinction following contextual fear conditioning in 5XFAD mice at <4 months of age. A, 5XFAD mice and their wild-type littermate mice were trained with one CS-US pairing for contextual fear conditioning. Mice were subjected to a single 30-min re-exposure to the conditioning context 1 day after training. Levels of freezing are plotted every 6 min through the 30-min extinction session. 5XFAD mice as well as wild-type control mice exhibit significant reductions in contextual freezing within the extinction session. B, Both wild-type and 5XFAD mice show significantly lower levels of freezing during the test session given 1 day after the 30-min re-exposure, as compared with the first 6-min of extinction session (n = 7–9 mice per group). * P < 0.05 versus the first 6-min of extinction. All data are presented as mean ± SEM.
Fig. 5
Fig. 5
Impairments of remote memory stabilization following contextual fear conditioning in 5XFAD mice at <4 months of age. 5XFAD mice and their wild-type littermate mice were trained with one CS-US pairing for contextual fear conditioning. 5XFAD mice show significantly lower levels of contextual freezing than wild-type mice when tested 30 days after training (n = 8–15 mice per group). * P<0.05 versus wild-type controls. All data are presented as mean ± SEM.
Fig. 6
Fig. 6
Impairments of remote memory stabilization following contextual fear conditioning in 5XFAD mice at 6 months of age. A, 5XFAD mice show levels of contextual freezing equivalent to those of wild-type mice when tested 1 day after training with three CS-US pairings (n = 15–17 mice per group). B, 5XFAD mice show significantly lower levels of freezing than wild-type mice when tested 30 day after training with three CS-US pairings (n = 13 mice per group). C, 5XFAD mice show significantly lower levels of freezing than wild-type mice when tested 30 day after training with five CS-US pairings (n = 14 mice per group). * P<0.05 versus wild-type controls. All data are presented as mean ± SEM.
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References

    1. Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005;20:187–198. - PubMed
    1. Anagnostaras SG, Maren S, Fanselow MS. Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. J Neurosci. 1999;19:1106–1114. - PMC - PubMed
    1. Ashe KH. Learning and memory in transgenic mice modeling Alzheimer’s disease. Learn Mem. 2001;8:301–308. - PubMed
    1. Battaglia F, Wang HY, Ghilardi MF, Gashi E, Quartarone A, Friedman E, Nixon RA. Cortical plasticity in Alzheimer’s disease in humans and rodents. Biol Psychiatry. 2007;62:1405–1412. - PubMed
    1. Bontempi B, Laurent-Demir C, Destrade C, Jaffard R. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature. 1999;400:671–675. - PubMed

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