Synaptic plasticity deficits via aberrant engagement of metaplasticity in the hippocampus of PS19 mice
TL;DR
It is demonstrated that transregional metaplasticity, as driven by prior activity in the stratum oriens (SO) in a way that inhibits subsequent LTP in wild-type mice, is occluded in PS19 mice, suggesting that the tauopathic hippocampus exists in a “metaplastic” state, which inhibits future LTP.
Abstract
Tauopathy is characterized by progressive synaptic failure and neuroinflammation, yet the laminar-specific nature of these disruptions remains poorly understood. We investigated hippocampal functional integrity and glial reactivity in 8–10-month-old PS19 (P301S) mice. Electrophysiological recordings in the CA1 stratum radiatum revealed an unexpected increase in basal synaptic transmission despite profound deficits in both maintenance and early induction of the LTP phase. Conversely, the dentate gyrus exhibited reduced basal transmission and impaired LTP maintenance, alongside significant paired-pulse plasticity changes not observed in CA1. Furthermore, we demonstrate that transregional metaplasticity, as driven by prior activity in the stratum oriens (SO) in a way that inhibits subsequent LTP in wild-type mice, is occluded in PS19 mice. These data suggest that the tauopathic hippocampus exists in a “metaplastic” state, which inhibits future LTP. Immunofluorescence studies revealed that while astrogliosis and microglial activation were pan-hippocampal, specific neuroinflammatory markers exhibited striking laminar specificity. Mean fluorescence intensity for the neuroinflammatory astrocyte marker C3 was significantly upregulated only in the SO, and the lysosomal marker CD68 showed heightened occupancy specifically in the SO and stratum lacunosum-moleculare. Our findings indicate that tau pathology does not affect the hippocampus uniformly. Instead, it induces region-specific shifts in synaptic efficacy and a breakdown of metaplastic control that coincides with anatomically localized neuroinflammatory signaling.