Increased excitability of dentate gyrus mossy cells occurs early in life in the Tg2576 model of Alzheimer’s disease

Abstract

ABSTRACTINTRODUCTIONHyperexcitability in Alzheimer’s disease (AD) emerge early and contribute to disease progression. The dentate gyrus (DG) is implicated in hyperexcitability in AD. We hypothesized that mossy cells (MCs), regulators of DG excitability, contribute to early hyperexcitability in AD. Indeed, MCs generate hyperexcitability in epilepsy.METHODSUsing the Tg2576 model and WT mice (∼1month-old), we compared MCs electrophysiologically, assessed c-Fos activity marker, Aβ expression and mice performance in a hippocampal-dependent memory task.RESULTSTg2576 MCs exhibit increased spontaneous excitatory events and decreased inhibitory currents, increasing the charge transfer excitation/inhibition ratio. Tg2576 MC intrinsic excitability was enhanced, and showed higher c-Fos, intracellular Aβ expression, and axon sprouting. Granule cells only showed changes in synaptic properties, without intrinsic changes. The effects occurred before a memory task is affected.DISCUSSIONEarly electrophysiological and morphological alterations in Tg2576 MCs are consistent with enhanced excitability, suggesting an early role in DG hyperexcitability and AD pathophysiology.HIGHLIGHTS∘MCs from 1 month-old Tg2576 mice had increased spontaneous excitatory synaptic input.∘Tg2576 MCs had reduced spontaneous inhibitory synaptic input.∘Several intrinsic properties were abnormal in Tg2576 MCs.∘Tg2576 GCs had enhanced synaptic excitation but no changes in intrinsic properties.∘Tg2576 MCs exhibited high c-Fos expression, soluble Aβ and axonal sprouting.