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. 2016 Mar 7;6:22728.
doi: 10.1038/srep22728.

Soluble Amyloid Beta Oligomers Block the Learning-Induced Increase in Hippocampal Sharp Wave-Ripple Rate and Impair Spatial Memory Formation

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Free PMC article

Soluble Amyloid Beta Oligomers Block the Learning-Induced Increase in Hippocampal Sharp Wave-Ripple Rate and Impair Spatial Memory Formation

Olivier Nicole et al. Sci Rep. .
Free PMC article

Abstract

Post-learning hippocampal sharp wave-ripples (SWRs) generated during slow wave sleep are thought to play a crucial role in memory formation. While in Alzheimer's disease, abnormal hippocampal oscillations have been reported, the functional contribution of SWRs to the typically observed spatial memory impairments remains unclear. These impairments have been related to degenerative synaptic changes produced by soluble amyloid beta oligomers (Aβos) which, surprisingly, seem to spare the SWR dynamics during routine behavior. To unravel a potential effect of Aβos on SWRs in cognitively-challenged animals, we submitted vehicle- and Aβo-injected mice to spatial recognition memory testing. While capable of forming short-term recognition memory, Aβ mice exhibited faster forgetting, suggesting successful encoding but an inability to adequately stabilize and/or retrieve previously acquired information. Without prior cognitive requirements, similar properties of SWRs were observed in both groups. In contrast, when cognitively challenged, the post-encoding and -recognition peaks in SWR occurrence observed in controls were abolished in Aβ mice, indicating impaired hippocampal processing of spatial information. These results point to a crucial involvement of SWRs in spatial memory formation and identify the Aβ-induced impairment in SWRs dynamics as a disruptive mechanism responsible for the spatial memory deficits associated with Alzheimer's disease.

Figures

Figure 1
Figure 1. Spatial recognition memory testing in a modified version of the Y-maze discrimination task.
(a) Recognition of the novel arm is long-lasting as shown by its persistence over increasing ITIs between encoding and recognition phases of the testing procedure in the 8-arm radial maze setup (n = 15 for ITI 10 min and 4 h, n = 14 for ITI 24 h and n = 11 for ITI 2 h, **p < 0.01; ***p < 0.001 versus chance level, t-tests (b) Silencing of hippocampal activity with lidocaine infused after encoding impairs recognition memory probed 4 hours later compared to mice injected with vehicle (aCSF)(n = 9/group, t16 = 5.85, ***p < 0.0001).
Figure 2
Figure 2. Aβos impair spatial recognition memory in a time-dependent manner.
(a) Immunoblot analysis of the Aβo solution injected intracerebroventrically showing the aggregation states of Aβos before and after 24 h of incubation at 4 °C. Monomers, dimers, trimers and tetramers were present in the freshly prepared solution. High molecular weight of Aβ(1–42) assemblies ranging from 30 to 100 kDa were also detected after 24 h of incubation. (b) Experimental design is shown. (c) While recognition memory performance in Aβ mice was similar to PBS-controls after 10 min (n = 6), it started to decrease as the ITI between encoding and test increased from 2 (n = 8–9) to 4 h. At the longer ITI, Aβ mice (n = 11) were severely impaired compared to PBS-control mice (n = 12), indicating faster forgetting (treatment x delay interaction F2,39 = 3.48, p < 0.05, **p < 0.01 versus PBS-controls).
Figure 3
Figure 3. Representative examples of hippocampal LFP and EMG during different sleep and awake states.
(a) Typical alternation in REM/SWS/awake over the 4 h time course separating encoding and recognition testing while the mouse remained in its home cage (see Fig. 5 for experimental paradigm). (bd) Representative examples of LFP from the hippocampal CA1 region (CA1) and EMG during SWS (b), REM (c) and awake states (d). (e) Representative recordings of SWRs in the CA1 region of the hippocampus. EMG: extracellular recordings from neck muscles; CA1: LFP and filtered LFP recorded from hippocampal pyramidal cell layers.
Figure 4
Figure 4. Characteristics of SWRs generated during baseline resting state in PBS-controls (gray bars, n = 13) and Aβo-injected (black bars, n = 10) mice.
(a) Experimental design is shown. Occurrence rate (b), frequency (c), duration (d) and normalized power (e) of SWS-Rs were not affected by the Aβ treatment (p > 0.2 for all comparisons, t-test).
Figure 5
Figure 5. Time course of SWRs occurrence rate over 40 min time bin prior and after the encoding and test phases of the spatial recognition memory procedure in vehicle- and Aβo-injected mice.
(a) Experimental design is shown. (b,c) Encoding- and recognition-induced peaks (depicted by dark gray and black bars, respectively) in SWR occurrence rates observed in PBS-controls (b), upper panel, *p < 0.05 versus other measurements, Bonferroni t-test, n = 7) were abolished in Aβo-injected mice (c), upper panel, NS versus all other measurements, Bonferroni t-test, n = 7). A similar pattern of effects of Aβos on SWRs was observed over shorter time bins of 20 min (lower panels). Note that for the first post-encoding and post-test 20 min bins, animals generally did not express SWS episodes, preventing the assessment of SWRs associated with SWS (the first SWS episodes occurred at 23.72 ± 2.23 min and 23.43 ± 1.61 min in vehicle- and Aβo-injected mice, respectively).
Figure 6
Figure 6. Time course of SWRs occurrence rate in 15 min bins of SWS.
This restrictive analysis enabled to control for the differential amount of SWS per time bin among recorded mice and revealed the same pattern of effects as depicted in Fig. 5. Encoding- and recognition-induced peaks of SWR occurrence are present in the PBS-control group (a), *p < 0.01 versus other measurement, Bonferroni t-test, n = 7) but abolished in the Aβ group (b), NS vs all other measurements, Bonferroni t-test, n = 7).

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