期刊
JOURNAL OF NEUROSCIENCE
卷 40, 期 26, 页码 5116-5136出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0425-20.2020
关键词
Alzheimer's; hippocampus; hyperactivity; interneuron; parvalbumin; sharp wave ripple
资金
- National Institutes of Health (NIH)/National Institute on Aging (NIA) [F31 AG062030]
- NIH/National Center for Advancing Translational Sciences [TL1 TR001431]
- ARCS Foundation
- NIH/National Institute of Neurological Disorders and Stroke (NINDS) [T32 NS041218]
- NIH/NIA [RF1 AG056603]
- NIH/NINDS [R01 NS108810]
Memory disruption in mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the microcircuitry underlying these disruptions is underexplored. We tested whether a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, and 8% decrease in duration of SWRs in ex vivo slices from male and female three-month 5xFAD mice versus littermate controls. 5xFAD mice of the same age were impaired in a hippocampal-dependent memory task. Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell recordings of PC and PV cells within the CAI region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs (sPCs) having a higher probability of spiking during SWRs. Both deep PCs (dPCs) and sPCs displayed an increased synaptic ER ratio, suggesting a dis-inhibitory mechanism. In contrast, we observed a 46% spike rate reduction during SWRs in PV basket cells (PVBCs), while PV bistratified and axo-axonic cells were unimpaired. Excitatory synaptic drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior studies of intrinsic PV cell dysfunction in AD, these findings suggest alterations to the PC-PVBC microcircuit also contribute to impairment.
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