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.