Neuronal Hyperexcitability and Seizure Susceptibility in a Novel Kcnt1 G269S Mouse Model

Kcnt1+/G269S mice show spontaneous behavioral seizures and greater thermal- and chemoconvulsant–induced seizure susceptibility than Kcnt1+/+ controls, with sex-linked respiratory abnormalities.

• Why it matters: KCNT1 pore-domain variants are linked to a wide epilepsy spectrum, but no in vivo model existed for the G288S-equivalent change, limiting mechanistic and outcome studies.
• What they did: A C57BL/6-Kcnt1em1Bryd mouse carrying Kcnt1 G269S (human G288S) was generated and tested using high-density microelectrode arrays in primary cortical neurons and behavioral assays across development and adulthood.
• The result: In vitro, Kcnt1+/G269S neurons displayed sustained hyperexcitability and hypersynchronous bursting, while Kcnt1G269S/G269S showed early excessive bursting followed by a progressive decline by 28 days-in-vitro.

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