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 brain regions to become dysfunctional 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 in early AD. Previously, we reported an increased long-term potentiation (LTP) magnitude at medial perforant path-dentate granule cell (MPP-DGC) synapses in slices from both male and acutely ovariectomized female TgF344-AD rats compared with wild type (Wt) as early as 6 months of age that is accompanied by an increase in steady-state postsynaptic depolarization during the high-frequency stimulation used to induce plasticity. Subsequently, we found that heightened function of β-adrenergic receptors (β-ARs) drives the increase in the LTP magnitude, but the increase in steady-state depolarization was only partially due to β-AR activation. As we previously reported no detectable difference in spine density or presynaptic release probability, we entertained the possibility that DGCs themselves might have modified passive or active membrane properties, which may contribute to the significant increase in charge transfer during high-frequency stimulation. Using brain slice electrophysiology from 6-month-old female rats acutely ovariectomized to eliminate variability due to fluctuating plasma estradiol, we found significant changes in passive membrane properties and active membrane properties leading to increased DGC excitability in TgF344-AD rats. Specifically, TgF344-AD DGCs have an increased input resistance and decreased rheobase, decreased sag, and increased action potential (AP) spike accommodation. Importantly, we found that for the same amount of depolarizing current injection, DGCs from TgF344-AD compared with Wt rats have a larger magnitude voltage response, which was accompanied by a decreased delay to fire the first action potential, indicating TgF344-AD DGCs membranes are more excitable. Taken together, DGCs in TgF344-AD rats are more excitable, which likely contributes to the heightened depolarization during high-frequency synaptic activation.

Dentate Gyrus Granule Cells Show Stability of BDNF Protein Expression in Mossy Fiber Axons with Age, and Resistance to Alzheimer’s Disease Neuropathology in a Mouse Model

“…In AD mouse models, there is increased excitability of GCs ( Nenov et al, 2015 ; Kim et al, 2021 ; Smith et al, 2022 ) and GCs specifically ( Minkeviciene et al, 2009 ; Alcantara-Gonzalez et al, 2021 ). When excitability is sufficiently elevated, seizures occur and the seizures increase GC ΔFosB ( You et al, 2017 ; Fu et al, 2019 ; Stephens et al, 2020 ).…”

In a circuit necessary for cognition and emotional affect, Alzheimer's-like pathology associates with neuroinflammation, cognitive and motivational deficits in the young adult TgF344-AD rat

“…A total of 33 (see Table 1 ) wild type (WT) and TgAD rats were used for behavioral and neurobiological experiments. As previously described ( Goodman et al, 2021 ; Smith and McMahon, 2018 ; Smith et al, 2022 ), TgAD rats containing the human Swedish mutation amyloid precursor protein (APP swe ) and the presenilin-1 exon 9 deletion mutant (PS1 ΔE9 ) were bred with WT F344 females (Envigo: previously Harlan Laboratories) at the University of Alabama at Birmingham. All breeding and experimental procedures were approved by the University of Alabama Institutional Animal Care and Use Committee and follow guidelines set by the National Institutes of Health.…”