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A key molecular determinant of NH is voltage\u2010gated Na+ channel 1.6 (Nav1.6), which mediates action potential firing in CA1 hippocampal neurons. Ameliorating NH through inhibition of the glycogen\u2010synthase kinase 3\u03b2 (GSK3\u03b2\/Nav1.6 complex may provide immediate benefits to cognition and memory and slow AD progression.<\/jats:p>\n <\/jats:sec>\n \n METHODS<\/jats:title>\n Hight\u2010throughput virtual screening and multiple in vitro biological assays were utilized to identify compound 1063. Patch\u2010clamp electrophysiology and electroencephalogram recordings were utilized to functionally assess 1063 in models of AD neuropathology.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n Building on previous studies identifying GSK3\u03b2 as a modulatory protein binding to the Nav1.6 C\u2010terminal domain (CTD), we identified 1063, a brain\u2010penetrant small molecule that inhibits GSK3\u03b2\/Nav1.6 complex assembly and reduces NH in AD rodent models.<\/jats:p>\n <\/jats:sec>\n \n DISCUSSION<\/jats:title>\n These results demonstrate the potential of the GSK3\u03b2\/Nav1.6 complex as a therapeutic target for NH in early\u2010stage AD.<\/jats:p>\n <\/jats:sec>\n \n Highlights<\/jats:title>\n \n \n \n The glycogen synthase kinase 3\u2010\u03b2 (GSK3\u03b2)\/Nav1.6 complex is a potential target for hyperexcitability in early Alzheimer's disease (AD).<\/jats:p>\n <\/jats:list-item>\n \n Compound 1063 dose\u2010dependently decreases GSK3\u03b2\/Nav1.6 complex 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