Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease with attenuation after rapamycin treatment in 5XFAD mice.

Increasing evidence indicates a bidirectional relationship between epilepsy and Alzheimer's disease (AD) with 22% of AD patients additionally suffering from seizures, which may be a targetable component of disease progression. Since epileptogenesis is associated with changes in excitatory: inhibitory (E:I) balance, we examined postmortem AD brain tissue from patients with and without seizure history and five times familial AD (5XFAD) mice for changes in several markers of E:I balance, including the inhibitory GABAA receptor, the chloride cotransporters, sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2), and the excitatory NMDA and AMPA type glutamate receptors. We hypothesized that seizure history in AD patients would be associated with greater E:I imbalances, and that such changes would also be observed in the 5XFAD mice following pentylenetetrazol (PTZ) kindling. We found that seizures in AD patients were associated with alterations in NKCC1 and KCC2 expression, indicative of depolarizing GABA, and exacerbated cognitive deficits. Seizures also significantly contributed to E:I imbalance in the 5XFAD mouse model, as similar changes in NKCC1 and KCC2 expression were found in PTZ treated 5XFAD mice, along with altered AMPA receptor protein expression indicative of calcium permeable-AMPA receptors. In addition, we found that chronic treatment with the mTOR inhibitor rapamycin at doses we have previously shown to attenuate seizure-induced β-amyloid pathology and cognitive deficits in 5XFAD mice, can mitigate the dysregulation of markers of E:I balance in this model. These data suggest that mTOR activation plays a role in modifying the E:I imbalance and network hyperexcitability in AD and that the FDA-approved mTOR inhibitors such as rapamycin may have potential for therapy in AD patients with a seizure history. ### Competing Interest Statement The authors have declared no competing interest.