Inhibitory parvalbumin basket cells are selectively impaired during hippocampal sharp wave ripples in a mouse model of familial Alzheimer's disease

Abstract

Memory disruption in mild cognitive impairment (MCI) and Alzheimers 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 micro-circuitry underlying these disruptions is under-explored. We tested if 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 3-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 CA1 region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs having a higher probability of spiking during SWRs. Both deep and superficial PCs displayed an increased synaptic E/I ratio, suggesting a disinhibitory 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 micro-circuit also contribute to impairment. Significance StatementWe demonstrate that a specific sub-type of inhibitory neuron, parvalbumin-expressing basket cells, have selectively reduced activity in a model of Alzheimers disease during activity critical for the consolidation of memory. These results identify a potential cellular target for therapeutic intervention to restore aberrant network activity in early amyloid pathology. While parvalbumin cells have previously been identified as a potential therapeutic target, this study for the first time recognizes that other parvalbumin neuronal sub-types, including bistratified and axo-axonic cells, are spared. These experiments are the first to record synaptic and spiking activity during sharp wave ripple events in early amyloid pathology and reveal that a selective decrease in excitatory synaptic drive to parvalbumin basket cells likely underlies reduced function.