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bioRxiv · 10.1101/2023.03.02.530499

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

Barbour, A. J.·Gourmaud, S.·Li, X.·Stewart, D. A.·Irwin, D. J.·Talos, D. M.·Jensen, F. E.
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Abstract

Approximately 22% of Alzheimers disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbate AD pathology and related cognitive deficits. Hence seizures may be a targetable component of AD progression. As epileptogenesis is associated with changes in neuronal excitatory: inhibitory (E:I) balance, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients and exacerbated further when seizures were a comorbidity. We similarly hypothesized that an E:I imbalance would be present in five times familial AD (5XFAD) mice and augmented following pentylenetetrazol (PTZ) seizure kindling. AD temporal cortical tissue from patients with or without seizure history and brain tissue from 5XFAD mice were examined 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 found that AD patients had decreased GABAA receptor subunits and those with comorbid seizures had worsened cognitive and functional scores, and increased in NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. The E:I imbalance appears to occur early in the disease course, as patch clamp recordings from CA1 neurons in hippocampal slices from prodromal 5XFAD mice showed decreased GABAergic inhibitory transmission and increased intrinsic excitability. In addition, seizure induction in prodromal 5XFAD mice further dysregulated NKCC1/KCC2, and altered the excitatory AMPA glutamate receptor protein expression, with a reduction in GluA2 subunit, indicative of calcium permeable-receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced -amyloid pathology and cognitive deficits, could reverse aspects of E:I imbalance in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that FDA-approved mTOR inhibitors hold therapeutic promise for AD patients with a seizure history.

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Barbour, A. J., Gourmaud, S., Li, X., Stewart, D. A., Irwin, D. J., Talos, D. M., Jensen, F. E.. 2023-03-03. Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease with attenuation after rapamycin treatment in 5XFAD mice.. https://doi.org/10.1101/2023.03.02.530499

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