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Increased excitability of dentate gyrus mossy cells occurs early in life in the Tg2576 model of Alzheimer's disease
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DOI：10.1186/s13195-025-01747-1.png)
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Abstract
En 中文
Background Hyperexcitability in Alzheimer's disease (AD) is proposed to emerge early and contribute to disease progression. The dentate gyrus (DG) and its primary cell type, granule cells (GCs) are implicated in hyperexcitability in AD. Hence, we hypothesized that mossy cells (MCs), important regulators of GC excitability, contribute to early hyperexcitability in AD. Indeed, MCs and GCs are linked to hyperexcitability in epilepsy. Methods Using the Tg2576 model of AD and WT mice (similar to 1 month-old), we compared MCs and GCs electrophysiologically and morphologically, assessed the activity marker c-Fos, A beta expression and a hippocampal- and MC-dependent memory task that is impaired at 3-4 months of age in Tg2576 mice. Results Tg2576 MCs had increased spontaneous excitatory events (sEPSP/Cs) and decreased spontaneous inhibitory currents (sIPSCs), increasing the excitation/inhibition ratio. Additionally, Tg2576 MC intrinsic excitability was enhanced. Consistent with in vitro results, Tg2576 MCs showed enhanced c-Fos protein expression. Tg2576 MCs had increased intracellular A beta expression, suggesting a reason for increased excitability. GCs showed increased excitatory and inhibitory input without changes in intrinsic properties, consistent with effects of increased MC activity. In support, increased GC activity was normalized by an antagonist of MC input to GCs. Also in support, Tg2576 MC axons showed sprouting to the area of GC dendrites. These effects occurred before an impairment in the memory task, suggesting they are extremely early alterations. Conclusions Alterations in Tg2576 MCs and GCs early in life suggest an early role for MCs in increased GC excitability. MCs may be a novel target to intervene in AD pathophysiology at early stages.
Keywords:
Hyperexcitability
Synaptic properties
Intrinsic properties
Granule cells
hAPP
Intracellular A beta
Novel object recognition
Spatial memory
Hippocampal slices
c-Fos expression
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