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.

Keywords: Alzheimer's disease; Bexarotene; Epilepsy; Hyperexcitability.

Figure 1

Bexarotene reduces interictal spike rate in hAPP J20 mice. A) Representative 15 seconds of baseline cortical spiking in hAPP J20 mouse. B) Representative 15 seconds of cortical EEG after 4 days of bexarotene treatment. Scale bar is 500μV, 1 second. C) Normalized spike rate plotted as a function of days of treatment with either placebo or bexarotene. Bexarotene treatment significantly decreased spike rate from pre-drug baseline (p<0.05), and days 3 and 4 were significantly lower than placebo values. D) Examples of time-frequency (Morlet wavelets) power spectra from representative hAPP J20 mouse baseline and day 5 of bexarotene. Power scale (right y axis) refers to μV²/Hz. E) Summarized relative frequency analysis (Welch power spectrum density) of major frequency bands (α,β,γ1,γ2,δ,θ) for hAPP J20 mice (n=5) on baseline and day 5.

Figure 2

Bexarotene reduces interictal spike rate in Kv1.1 null mice. A) Representative 15 second interval of baseline cortical spiking, and B) after bexarotene treatment for 3 days. Scale bar is 500μV, 1 second. C) Normalized spike rate plotted as a function of days of treatment with either placebo or baseline. The overall trend of bexarotene treatment was significantly reduced (p<0.05) and days 3, 4, and 5 were significantly lower than placebo values (p<0.05). D) Seizures were significantly reduced in bexarotene treated (0. 458 ± 0.18) versus placebo treated (1.38 ± 0.49) as normalized by recording sessions (p<0.05). E) Kv1.1 null mice were treated once (day 1) with bexarotene and recorded from over 5 subsequent days. No significant effect was found with only a single treatment. F) Examples of time frequency (Morlet wavelets) power spectra from a representative Kv1.1 null mouse baseline and day 5 of bexarotene. Power scale (right y axis) refers to μV²/Hz. G) Summarized relative frequency analysis (Welch power spectrum density) of major frequency bands (α,β,γ1,γ2,δ,θ) for Kv1.1 null mice (n=6) on baseline and day 5.