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. 2015 Nov:125:152-162.
doi: 10.1016/j.nlm.2015.09.003. Epub 2015 Sep 15.

Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice

Jason K Clark #  1 , Matthew Furgerson #  2   3 , Jonathon D Crystal  4 , Marcus Fechheimer  3 , Ruth Furukawa  3 , John J Wagner  1
Affiliations

Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice

Jason K Clark et al. Neurobiol Learn Mem. 2015 Nov.

Abstract

Alzheimer's disease is a neurodegenerative condition believed to be initiated by production of amyloid-beta peptide, which leads to synaptic dysfunction and progressive memory loss. Using a mouse model of Alzheimer's disease (3xTg-AD), an 8-arm radial maze was employed to assess spatial working memory. Unexpectedly, the younger (3month old) 3xTg-AD mice were as impaired in the spatial working memory task as the older (8month old) 3xTg-AD mice when compared with age-matched NonTg control animals. Field potential recordings from the CA1 region of slices prepared from the ventral hippocampus were obtained to assess synaptic transmission and capability for synaptic plasticity. At 3months of age, the NMDA receptor-dependent component of LTP was reduced in 3xTg-AD mice. However, the magnitude of the non-NMDA receptor-dependent component of LTP was concomitantly increased, resulting in a similar amount of total LTP in 3xTg-AD and NonTg mice. At 8months of age, the NMDA receptor-dependent LTP was again reduced in 3xTg-AD mice, but now the non-NMDA receptor-dependent component was decreased as well, resulting in a significantly reduced total amount of LTP in 3xTg-AD compared with NonTg mice. Both 3 and 8month old 3xTg-AD mice exhibited reductions in paired-pulse facilitation and NMDA receptor-dependent LTP that coincided with the deficit in spatial working memory. The early presence of this cognitive impairment and the associated alterations in synaptic plasticity demonstrate that the onset of some behavioral and neurophysiological consequences can occur before the detectable presence of plaques and tangles in the 3xTg-AD mouse model of Alzheimer's disease.

Keywords: Alzheimer’s disease; Amyloid-beta; Hippocampal slice; Radial maze; Synaptic plasticity; Transgenic mouse model.

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Figures

Figure 1
Figure 1
Short-term and working memory results in the 8-arm radial maze. The Schematic above each data set illustrates the protocol used for testing. (•) represents baited arms. Blacked out arms represent inaccessible arms. A and B) 8-arm uninterrupted task results for 3xTg-AD and NonTg control mice at 3 and 8 months. A) NonTg (black bars, n=11) and 3xTg-AD (open bars, n=12) mice at 3 months old. B) NonTg (black bars, n=11) and 3xTg-AD (open bars, n=11) at 8 months old. Both the NonTg and 3xTg-AD mice significantly improved their performance as the number of training sessions increased. C and D) Test phase results of the delayed spatial win-shift protocol for 3xTg-AD and NonTg control mice at 3 and 8 months. C) NonTg (black bars, n=11) and 3xTg-AD (open bars, n=12) mice at 3 months old. D) NonTg (black bars, n=11) and 3xTg-AD (open bars, n=11) mice at 8 months old. The NonTg mice significantly improved their performance as the number of training sessions increased. In contrast, the 3xTg-AD mice do not improve at either 3 or 8 months. In addition, there is a significant difference between the performance of the NonTg and the 3xTg-AD mice at days 19-20 at 8 months. Bar graph values represent the mean ± SEM of the first 2 days or the last 2 days of testing. Significance was determined using a mixed ANOVA or independent t-test (* p < 0.05, ** p < 0.01).
Figure 2
Figure 2
Aβ42 quantification and relation to maze performance in 3xTg-AD and NonTg control mice. A) Comparison of total Aβ42 levels in ventral hippocampal tissue at 3 and 8 months of age for 3xTg-AD (open bars, 3 months n=12, 8 months n=11) and NonTg (black bars, 3 months n=8, 8 months n=10) mice. Bar graph values represent the mean ± SEM, significance was determined using ANOVA (** p < 0.01). B) Scatter plot showing the relationship between total Aβ42 and total errors in the test phase at 3 and 8 months in 3xTg-AD (open/dark grey circles) and NonTg (black/light grey circles) mice. Significance was determined using ANOVA. Both 3 (p < 0.05) and 8 (p < 0.01) month 3xTg-AD mice show a significant correlation between total Aβ42 and total errors.
Figure 3
Figure 3
Field Excitatory Post Synaptic Potentials (fEPSP) recorded from the CA1 region of ventral hippocampus in 3xTg-AD and NonTg control mice. A) Stimulus response curves for 3xTg-AD (open circles, n=54(12)) and NonTg (black circles, n=56(11)) control mice at 3 months of age. Input intensities are 40, 50, 60, 75, 90, 110, 130, and 150 μA. The averaged fEPSP sweeps are shown above the stimulus response curves. B) Same as panel A except at 8 months of age for 3xTg-AD (n=39(11)) and NonTg (n=47(11)) control mice. The values represent the mean ± SEM from n slices. Significance between genotypes was determined using an independent t-test (* p < 0.05, ** p < 0.01).
Figure 4
Figure 4
Paired-pulse Field Excitatory Post-Synaptic Potentials (fEPSP) recorded from the CA1 region of ventral hippocampus in 3xTg-AD and NonTg control mice. A) Paired-pulse ratios at 50, 100, 200, and 500 ms intervals in 3xTg-AD (open bars, n=54(12)) and NonTg (black bars, n=58(11)) control mice at 3 months of age. The averaged fEPSP sweeps are shown above the paired-pulse ratios. B) Same as panel A except at 8 months of age for 3xTg-AD (n=36(11)) and NonTg (n=42(11)) control mice. Bar graph values represent the mean ± SEM from n slices. Significance between genotypes was determined using an independent t-test (* p < 0.05, ** p < 0.01).
Figure 5
Figure 5
Long-Term Potentiation (LTP) of Field Excitatory Post-Synaptic Potentials (fEPSP) recorded from the CA1 region of ventral hippocampus in 3xTg-AD and NonTg control mice. A) Summary plot of normalized fEPSP slope values in 3 month old NonTg mice for total LTP (black circle, (n=25(10)) and bath applied D,L-AP5 (50 μM) representing non-NMDAR LTP (light grey circle, n=25(10)), before and after high frequency stimulation (HFS) (4 x 200Hz/0.5 s at 5 s intervals) indicated by the arrow at 30 minutes. The averaged fEPSP sweeps before and after HFS for total LTP and non-NMDAR LTP are shown above the plot. B) Same as panel A except in 3 month old 3xTg-AD mice for total LTP (open circle, (n=23(12)) and non-NMDAR LTP (dark grey circle, n=25(12)). C) Summary quantification of total LTP and non-NMDAR LTP for NonTg and 3xTg-AD mice at 1 hr post-HFS. D, E, & F) Same as A, B, & C above except at 8 months of age. For NonTg (total LTP, n=17(9); non-NMDAR LTP, n=23(11)) control mice, and 3xTg-AD (total LTP, n=15(11); non-NMDAR LTP, n=18(11)) mice. Bar graph values represent the mean ± SEM from n slices. Significance was determined using a 2 way ANOVA (* p < 0.05, ** p < 0.01).
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