Resilient Hippocampal Gamma Rhythmogenesis and Parvalbumin-Expressing Interneuron Function Before and After Plaque Burden in 5xFAD Alzheimer’s Disease Model

Abstract

Recent studies have implicated impaired Parvalbumin Fast-Spiking Interneuron (PVIN) function as a precipitating factor underlying abnormalities in network synchrony, oscillatory rhythms, and cognition associated with Alzheimer’s disease (AD). However, a complete developmental investigation of potential gamma deficits, induced by commonly used carbachol or kainate in ex vivo slice preparations, within AD model mice is lacking. We examined gamma oscillations using field recordings in acute hippocampal slices from 5xFAD and control mice, through the period of developing pathology, starting at 3 months of age, when there is minimal plaque presence in the hippocampus, through to 12+ months of age, when plaque burden is high. In addition, we examined PVIN participation in gamma rhythms using targeted cell-attached recordings of genetically-reported PVINs, in both wild type and mutant mice. In parallel, a developmental immunohistochemical characterisation probing the PVIN-associated expression of PV and perineuronal nets (PNNs) was compared between control and 5xFAD mice. Remarkably, this comprehensive longitudinal evaluation failed to reveal any obvious correlations between PVIN deficits (electrical and molecular), circuit rhythmogenesis (gamma frequency and power), and Aβ deposits/plaque formation. By 6–12 months, 5xFAD animals have extensive plaque formation throughout the hippocampus. However, a deficit in gamma oscillatory power was only evident in the oldest 5xFAD animals (12+ months), and only when using kainate, and not carbachol, to induce the oscillations. We found no difference in PV firing or phase preference during kainate-induced oscillations in younger or older 5xFAD mice compared to control, and a reduction of PV and PNNs only in the oldest 5xFAD mice. The lack of a clear relationship between PVIN function, network rhythmicity, and plaque formation in our study highlights an unexpected resilience in PVIN function in the face of extensive plaque pathology associated with this model, calling into question the presumptive link between PVIN pathology and Alzheimer’s progression.

Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology

“…Interestingly, no changes were observed in either the amplitude or frequency of excitatory and inhibitory spontaneous synaptic events (Fig. 6 H, I ) echoing recent work from 3-month-old 5xFAD mice in hippocampal slices, where local circuit behavior and oscillations were also largely resilient to change 95 . This may be due to several factors, including the relatively low AP frequency of evoked PV firing in the slice.…”

Targeting Galectin-3 to Counteract Spike-Phase Uncoupling of Fast-Spiking Interneurons to Gamma Oscillations in Alzheimer's Disease

“…The shift in the limits for the bandwidth power calculations to 20-80 Hz compared with in vivo (commonly ⁓30-80 Hz) is due to the linear relationship between recording temperature and oscillation frequency [58,59]. In our experimental set-up, the optimal recording temperature was ⁓6 °C lower than the body temperature, and the bandwidth used for gamma power calculation is a routinely used frequency band in ex vivo recordings of gamma rhythms [52,55,[59][60][61][62][63]. Thus, in control conditions all the slices included in the study showed a peak frequency between 20 and 80 Hz.…”

Local and long-range GABAergic circuits in hippocampal area CA1 and their link to Alzheimer’s disease

“…Moreover, in APP/PS1 mice (AD model with human amyloid-beta precursor protein and presenilin-1 mutations), PV INs show close interactions with microglia (Gervais et al, 2022). However, another study has called in to question the relationship between PV INs and AD pathogenesis (Mackenzie-Gray Scott et al, 2022). Of note, PV INs also express amyloid-degrading enzymes which would indeed be counterintuitive (Pacheco-Quinto et al, 2016).…”