Abstracts

Rationale: It has been proposed that hyperexcitability in Alzheimer’s disease (AD) emerges early in the pathophysiological process and contributes to further disease progression. Hyperexcitabililty is manifested as epileptiform activity and seizures in both humans and animal models. The hippocampal dentate gyrus (DG) is implicated in the generation of hyperexcitability in AD, and we showed that early in the development of the Tg2576 mouse model of AD (3 months of age) the granule cells (GCs, the main cell type in the DG) already showed synaptic changes reflecting enhanced excitatory activity. Mossy cells (MCs) of the DG hilus are important regulators of GC activity and highly vulnerable to diverse pathological conditions such as brain injury and epilepsy. Thus, the purpose of this study was to evaluate whether MCs are affected at early stages of AD in the Tg2576 mouse model.


Methods: WT and Tg2576 mice were used at ~1 month of age. MCs were characterized by whole-cell patch-clamp recordings in hippocampal slices. Intrinsic properties (RMP, input resistance, tau, action potential (AP) amplitude, half-width, rheobase, threshold, and the maximum rising and decay slopes of the APs), AP firing, and synaptic properties (frequency and amplitude of spontaneous excitatory postsynaptic potentials, sEPSPs, and excitatory and inhibitory postsynaptic currents, sEPSCs and sIPSCs) were determined. In separate animals, expression of the activity marker c-Fos, amyloid b (Aβ), and MC axonal distribution was assessed using immunofluorescence. Finally, a hippocampal-dependent memory task, novel object recognition, was also evaluated.


Results: Tg2576 MCs exhibit increased sEPSP frequency and decreased sIPSC frequency and amplitude in comparison to WT mice. Intrinsic excitability was enhanced, reflected by a depolarized resting membrane potential and reduced rheobase. There was a significantly enhanced AP firing frequency induced by current injection in Tg2576 MCs. Consistent with these findings, c-Fos protein expression was higher in the Tg2576 hilus than WT mice. C-Fos was also elevated in the GC layer so GCs were further examined. GCs showed increased excitatory and inhibitory input frequency, consistent with greater activity of MCs because MCs directly activate and indirectly inhibit GCs. Tg2576 MCs demonstrated intracellular Ab, although extracellular amyloid plaques do not develop until after 6 months of age in this mouse model. MC axons expanded their terminal plexus in the GC dendritic layer in Tg2576 mice compared to WT mice. These effects occurred before any change in the memory task, suggesting they are extremely early alterations.


Conclusions: Early electrophysiological and anatomical alterations in Tg2576 MCs suggest an early role of MCs in AD pathophysiology.


Funding: This project was supported by the Alzheimer’s Association grant (AARFD-22-926807) to DAG, and NIH R01 AG-055328 to HES.