Selective disruption of tau-SH3 interactions rescues seizure and sleep phenotypes.

AxxA6 tau knock-in mice, with proline-to-alanine changes in the sixth PxxP motif, show kainic acid seizure resistance and improved REM beta power and sleep.

• Why it matters: Seizures and sleep disruption in Alzheimer’s disease worsen network dysfunction and cognitive decline, but tau-lowering approaches risk impairing tau’s normal physiological roles.
• What they did: The study created AxxA6 and R221A tau knock-in mice, mapped tau–SH3 interactions in hippocampal neurons and cortical lysates, then tested epilepsy using Kv1.1 heterozygous knockout crosses with 24 h EEG and kainic acid (25 mg/kg).
• The result: AxxA6 and R221A reduced tau binding to SH3 proteins BIN1, PLCγ1, and p85α/PI3K, with AxxA6 specifically lowering Fyn interaction (P < 0.0001), and both variants prevented picrotoxin/4-AP–driven epileptiform bursting (P < 0.05) while preserving motor and cognitive measures across ageing.

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