title: Elevated Neuronal Excitability Due to Modulation of the Voltage-Gated Sodium Channel Nav1.6 by Aβ1-42.
abstract: Aberrant increases in neuronal network excitability may contribute to the cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability are not fully understood. Such overexcitation of neuronal networks has been detected in the brains of APP/PS1 mice. In the present study, using current-clamp recording techniques, we observed that 12 days in vitro (DIV) primary cultured pyramidal neurons from P0 APP/PS1 mice exhibited a more prominent action potential burst and a lower threshold than WT littermates. Moreover, after treatment with Aβ1-42 peptide, 12 DIV primary cultured neurons showed similar changes, to a greater degree than in controls. Voltage-clamp recordings revealed that the voltage-dependent sodium current density of neurons incubated with Aβ1-42 was significantly increased, without change in the voltage-dependent sodium channel kinetic characteristics. Immunohistochemistry and western blot results showed that, after treatment with Aβ1-42, expressions of Nav and Nav1.6 subtype increased in cultured neurons or APP/PS1 brains compared to control groups. The intrinsic neuronal hyperexcitability of APP/PS1 mice might thus be due to an increased expression of voltage-dependent sodium channels induced by Aβ1-42. These results may illuminate the mechanism of aberrant neuronal networks in AD.
authors.affiliation: Department of Physiology, Dalian Medical University Dalian, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Physiology, Dalian Medical University Dalian, China.
authors.forename: Xiao-Gang
authors.initials: XG
authors.lastname: Zhang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Dalian Medical University Dalian, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Dalian Medical University Dalian, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Physiology, Dalian Medical University Dalian, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Jang
authors.affiliation: The Key Laboratory of Stem Cell and Regenerative Medicine, Kunming Medical College, Institute of Molecular and Clinical Medicine Kunming, China.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Xiao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Second Affiliated Hospital, Soochow University Suzhou, China.
authors.forename: Quan-Hong
authors.initials: QH
authors.lastname: Ma
authors.affiliation: Department of Physiology, Dalian Medical University Dalian, China.
authors.forename: Shao
authors.initials: S
authors.lastname: Li
keywords: Alzheimer's disease; beta-amyloid peptide; excitability; neurodegeneration; voltage-gated sodium channel