Targeting Nav1.6: a promising strategy against cognitive impairment in maternal separation-sensitive mice.

BACKGROUND: Maternal separation (MS) correlates with adult cognitive impairment and neuroinflammation. The voltage-gated sodium channel Nav1.6 is critical in neuroinflammatory and neurodegenerative processes, but its role in MS-induced cognitive impairment is unclear. This study investigated whether hippocampal AAV-shRNA-mediated Nav1.6 reduction protects against MS-induced cognitive deficits in mice, exploring mechanisms involving hippocampal neuroinflammation, autophagy-related markers, and apoptosis-related changes. METHODS: C57BL/6 mice (male/female) were subjected to daily MS (3 h/day, postnatal days 1-21). Nav1.6 was knocked down via stereotactic injection of AAV-GP-2-SCN8A-mus into the hippocampus of MS-sensitive mice (6 weeks). Cognitive function was evaluated using Morris water maze, novel object recognition, Y-maze, and open field tests. Hippocampal synaptic plasticity (LTP), protein expressions (Nav1.6, LC3B, p62, PSD95, Syn, Bax, Bcl-2), and inflammatory cytokines were analyzed via electrophysiology, Western blotting, RT-PCR, and ELISA, respectively. RESULTS: MS-sensitive mice exhibited significant cognitive deficits, reduced hippocampal synaptic plasticity, and increased Nav1.6 immunoreactivity in Iba1-positive cells. Hippocampal Nav1.6 reduction improved cognitive function, altered autophagy-related markers (reduced LC3B-II and elevated p62), altered apoptosis-related markers, and mitigated neuroinflammation (reduced IL-6, TNF-α, IL-1β). CONCLUSIONS: Hippocampal Nav1.6 reduction alleviates MS-induced cognitive impairment and is associated with modulation of autophagy- and apoptosis-related changes and neuroinflammatory responses, suggesting Nav1.6 as a potential therapeutic target for stress-related cognitive disorders.