Amyloid β-Induced Upregulation of Na v 1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer’s Disease Mouse Model

Hyperexcitability and alterations in neuronal networks contribute to cognitive impairment in Alzheimer’s Disease (AD). Voltage-gated sodium channels (Na V ), which are crucial for regulating neuronal excitability, have been implicated in AD-related hippocampal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we show by using primary hippocampal neurons exposed to amyloid-β 1–42 (Aβ 1–42 ) oligomers and from Tg2576 mouse embryos, that the selective upregulation of Na V 1.6 subtype contributes to membrane depolarization and to the increase of spike frequency, thereby resulting in neuronal hyperexcitability. Interestingly, we also found that Na V 1.6 overexpression is responsible for the aberrant neuronal activity observed in hippocampal slices from 3-month-old Tg2576 mice. These findings identify the Na V 1.6 channels as a determinant of the hippocampal neuronal hyperexcitability induced by Aβ 1–42 oligomers. The selective blockade of Na V 1.6 overexpression and/or hyperactivity might therefore offer a new potential therapeutic approach to counteract early hippocampal hyperexcitability and subsequent cognitive deficits in the early stages of AD.