Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy

Abstract

The nuclear retinoid X receptor agonist, bexarotene, has been implicated in recovery of cognitive function in mouse models of Alzheimer's disease (AD). Since AD genetic mouse models also show abnormal neural hyperexcitability, which may play a destructive role in memory storage and retrieval, we studied whether bexarotene exerted dynamic network effects on electroencephalography cortical spike discharge rate and spectral frequency in an AD (hAPP J20 model) and non-AD (Kv1.1 null) mouse models of epilepsy. We find that oral treatment with bexarotene over 1 week acutely reduced spike discharges in both models and seizures in the Kv1.1 null mouse model without major alterations in the background frequency of brain rhythms. The effect was reversible and exhibited a similar rapid onset in hippocampal slices. While the exact mechanisms are unknown, bexarotene counteracts both amyloid-β-induced and amyloid-β-independent increases in cortical network hyperexcitability.