Abstract
Mouse Alzheimer's disease (AD) models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3–6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4–6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: ‘direct’) and long-latency (presumably polysynaptic: ‘re-entrant’) responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice could be due to the development of an abnormal hyper-excitable state in the hippocampal formation.
Highlights
Alzheimer’s disease (AD) is characterised phenotypically by profound declarative memory deficits
Current-response relationship To examine the integrity of CA1 sr/slm-dentate gyrus (DG) hippocampal circuitry, amplitude and latency of responses to activation of PP fibres were determined over a range of current intensities
There were no significant differences in amplitude measurements between control and 3xTgAD animals for CA1 stratum radiatum (CA1sr), CA1 stratum lacunosum-moleculare (CA1slm) or DG responses in either young or old mice (Figure 2A–F; genotype (2) by PPulses were delivered at inter-pulse-intervals (PPI) (5) mixed ANOVA)
Summary
Alzheimer’s disease (AD) is characterised phenotypically by profound declarative memory deficits. Hippocampal output can return to surrounding neocortex via deep layers of EC and/or re-enter the hippocampal formation via projections from deep to superficial EC [9,10] The latter reverberation (or ‘re-entrance’) is considered to be pivotal in memory formation, possibly acting as a comparator mechanism to allow processed input to be evaluated alongside new information and/or as a memory consolidation mechanism during sleep [7,11,12,13]. Functional abnormalities have been detected in the hippocampus during memory encoding in human AD patients [19] It is of major interest, to determine the pathophysiological profile of the hippocampal formation in AD models and to elucidate, in particular, whether reverberation (re-entrance) occurs in control and AD model mice
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