Hippocampal Microcircuit Alterations in Early Amyloid Pathology: A Selective Impairment of Parvalbumin-Expressing Basket Cells During Sharp Wave Ripple Events

Abstract

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 remains under-explored. In this dissertation, I tested the hypothesis that a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. Employing the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells, I 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, I 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 excitatory-to-inhibitory (E/I) ratio, suggesting a disinhibitory mechanism. In contrast, I 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. Preliminary staining suggests perineuronal nets (PNNs), which preferentially ensheathe PVBCs and support function, are degraded in 5xFAD mice. Together these findings suggest alterations to the PC-PVBC microcircuit contribute to impairment in early amyloid pathology.