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bioRxiv · 10.64898/2026.07.28.741298

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

Tang, J.·Swope, C. B.·Patel, K.·Ahmad Jafri, A. J.·Xiang, J.·Milner, T. A.·Hemmings, H. C.·Platholi, J.
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Abstract

Neuronal hyperexcitability is an early and pervasive feature of Alzheimers 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 A{beta} expression, assessed by immunolabeling, was sparse at three months and rose significantly by seven months, indicating that CA3 hyperactivity emerges before substantial oligomeric A{beta} 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.

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Tang, J., Swope, C. B., Patel, K., Ahmad Jafri, A. J., Xiang, J., Milner, T. A., Hemmings, H. C., Platholi, J.. 2026-07-29. Increased expression of developmental Nav1.3 promotes hippocampal CA3 hyperexcitability in early-stage 5xFAD mice. https://doi.org/10.64898/2026.07.28.741298

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