Increased expression of developmental Nav1.3 promotes hippocampal CA3 hyperexcitability in early-stage 5xFAD mice

Neuronal hyperexcitability is an early and pervasive feature of Alzheimer's disease (AD) that both predicts and accelerates subsequent cognitive decline. Persistent excitability depends on activation of voltage-gated sodium channels (Nav), yet most work has focused on the Nav subtypes expressed in the mature brain. Here, we show that Nav1.3, a subtype normally confined to early development, shows aberrantly increased expression in the dentate gyrus (DG)-CA3 circuit in early-stage 5xFAD mice. Using in vivo fiber photometry, three-month-old 5xFAD mice exhibited greater CA3 neuron population activity than seven-month-old 5xFAD mice or wildtype littermates. Oligomeric Aβ expression, assessed by immunolabeling, was sparse at three months and rose significantly by seven months, indicating that CA3 hyperactivity emerges before substantial oligomeric Aβ accumulates. This early activity increase coincided with elevated Nav1.3 expression at the DG-CA3 mossy fiber synapse, localized by immuno-electron microscopy to presynaptic mossy fiber terminals, where it exceeded levels in age-matched controls. Lentiviral shRNA-mediated knockdown of Nav1.3 expression in CA3 normalized CA3 network activity in early-stage 5xFAD mice. These findings identify Nav1.3 expression at DG-CA3 mossy fiber synapses as a driver of early hippocampal network dysfunction in AD and suggest Nav1.3 modulation as a potential target for circuit-level intervention.