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.

Hyperprolinaemia is characterized by increased tissue accumulation of proline (Pro) and is known to exert serious cognitive and/or neuropsychiatric symptomatology as a direct result of Pro accumulation in the brain. The aim of this study was to explore a putative link between experimentally-simulated hyperprolinaemia and the activity of acetylcholinesterase (AChE); a crucial neurotoxicity marker. In vitro experiments were undertaken on purified eel-derived AChE, as well as on adult mouse brain homogenates, in order to examine the effect of a spectrum of Pro concentrations (3, 30, 500, and 1000 μM) on this marker. Our data showed that although Pro exerted a significant inhibitory effect on pure AChE activity, mouse brain-derived membrane-bound AChE activity was found either unaltered or significantly increased following incubation with Pro. The use of AChE activity as a neurotoxicity marker within the context of experimentally-simulated hyperprolinaemia should be considered with caution and in parallel with a number of other experimental parameters.

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