Reduced expression of α5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior

Gabra5−/− mice exhibit•Elevated 0-2 Hz EEG activity during all sleep-wake states•Lower 8-12 Hz EEG activity during rapid-eye-movement sleep•Reduced spindle-like oscillations during non-rapid-eye-movement sleep•Normal alterations in EEG activity following intraperitoneal injection of lipopolysaccharide

A reduction in the activity of GABAA receptors, particularly α5 subunit-containing GABAA receptors (α5GABAARs), has been implicated in the etiology of Autism Spectrum Disorders (ASD). Genetically modified mice that lack α5GABAARs (Gabra5−/−) exhibit autism-like behaviors and both enhanced and impaired learning and memory, depending on the behavioral task. The aim of this study was to examine the electroencephalogram (EEG) activity and sleep-wake behaviors in Gabra5−/− mice and wild-type mice. In addition, since some individuals with ASD can exhibit elevated innate immune response, mice were treated with lipopolysaccharide (LPS; 125 mg/kg intraperitoneal injection) or vehicle and EEG and sleep-wake patterns were assessed. The results showed that Gabra5−/− mice (n = 3) exhibited elevated 0-2 Hz EEG activity during all sleep-wake states (all p < 0.04), decreased 8-12 Hz EEG activity during REM sleep (p = 0.04), and decreased sleep spindles under baseline conditions compared to wild-type controls (n = 4) (all p ≤ 0.03). Alterations in EEG activity and sleep-wake behavior were identified in Gabra5−/− mice following treatment with LPS, however these changes were similar to those in wild-type mice. Our findings support the hypothesis that reduced α5GABAAR activity contributes to an ASD phenotype. The results also suggest that Gabra5−/− mice may serve as an animal model for ASD, as assessed through EEG activity and sleep-wake behaviors.