Dentate Granule Cells Are Hyperexcitable in the Tgf344-Ad Rat Model of Alzheimer’s Disease

Abstract

The dentate gyrus is both a critical gatekeeper for hippocampal signal processing and one of the first regions to dysfunction in Alzheimer's disease (AD). Accordingly, the appropriate balance of excitation and inhibition through the dentate is a compelling target for mechanistic investigation and therapeutic intervention of early AD. Previously, we reported increased LTP magnitude at medial perforant path-dentate granule cell (MPP-DGC) synapses in slices from TgF344-AD rats compared to Wt as early as 6 months. We next determined that the enhanced LTP magnitude was due to heightened function of β-ARs leading us to ask if dentate granule cells (DGCs) also have modified passive or active membrane properties which may also contribute to hyperexcitability or aberrant hippocampal processing. Although there was no detectable difference in spine density and presynaptic release probability, dentate granule cells (DGCs) themselves might have increased electrical response to synaptic input during LTP induction, which was measured as a significant increase in charge transfer during high-frequency stimulation. In this study, we found passive membrane properties and active membrane properties are altered, leading to increased TgF344-AD DGC excitability. Specifically, TgF344-AD DGCs have an increased input resistance and decreased rheobase, decreased sag, and increased action potential (AP) spike accommodation. Importantly, we find that the voltage response increased in DGCs from TgF344-AD compared to Wt accompanied by decreased delay to fire the first AP, indicating that for the same amount of depolarizing current injection TgF344-AD DGCs membranes are more excitable. Taken together, DGCs of TgF344-AD rats are more excitable, but due to heightened accommodation, may be unable to discharge at high frequency for longer durations of time, compared to their Wt littermates.

Dynamic sensitivity analysis: Defining personalised strategies to drive brain state transitions via whole brain modelling

“…Evidence supports the hypothesis that either direct stimulation within Globus Pallidus internus (GPi) or the Subthalamic Nucleus (STN), reduces the GPi inhibitory output neurons activity and therefore increases the thalamic target neurons activity, remarking the inhibitory role of DBS. The local inhibition may be caused by various processes, for example the inactivation of voltage-gated currents [89] , activation of inhibitory afferents [90] and sustained depolarization of neuronal cell membranes [91] . Conversely, evidence also supports the excitatory effect of DBS, for example when stimulating the STN neurons, the GPi, Globus Pallidus externa (GPe), Substantia Nigra (SNr) firing rates increase [92] .…”