Sexual and developmental variability of spike-wave discharges in the taiep rat: A model of H-ABC leukodystrophy.

Abstract

Taiep rat has a leukodystrophy caused by a tubulinopathy affecting the β-tubulin 4 A (TUBB4A) gene characterized by hypomyelination and progressive demyelination of the central nervous system. In magnetic resonance imaging taiep rats showed hypomyelination and atrophy of the putamen and cerebellum that resemble human leukodystrophy named hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). In addition, taiep rat has spike-wave discharges (SWDs) in the electroencephalogram (EEG) associated with behavioral interruption of the ongoing activity. This study aims to analyze the characteristics and circadian distribution of SWDs in both sexes throughout the first year of life. We chronically implanted male and female taiep rats aged 3, 6, 9, and 12 months with electrodes in the cerebral cortex, neck muscles, and right eye orbit for 24-hour video-EEG recordings. Offline, we analyzed the number, mean and total duration of SWDs, the latency of the first SWD, and the spectral content using Fast Fourier Transform. A cosinor analysis was applied to 24-hour data to describe circadian distributions of SWD number and mean duration. In both sexes, the number, mean, and total duration of SWDs increased with age; onset occurred earlier in males at 3 months with respect to females that have SWDs at 6 months. The acrophase of the mean duration rhythm was delayed in females. These findings indicate a sexual dimorphism in the SWDs expression and timing during the circadian cycle. In both sexes, the interspike frequency of SWDs was 6.31 showing no change with age, suggesting similar thalamo-cortical circuit properties across all groups. In conclusion, these results clearly demonstrate that hypomyelination and demyelination affect the expression and circadian dynamics of SWDs in both sexes throughout development in taiep rats. In conclusion, taiep rats had a leukodystrophy associated to spike-wave discharges and behavioral arrest that are absence-like epilepsy.