Region-dependent differences in tonic inhibition underlie epileptic features in Angelman syndrome model mice

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Epilepsy and abnormal electroencephalographic (EEG) rhythms are key features, but their mechanisms and treatment remain unclear. Previous work showed that extrasynaptic γ-aminobutyric acid type A (GABA_A) receptor-mediated tonic inhibition is reduced in cerebellar granule cells of AS model mice, contributing to motor deficits. Here, we evaluated tonic inhibition across brain regions and tested whether its dysregulation drives epilepsy, EEG abnormalities, and behavioral deficits in AS.

Tonic inhibition was measured in principal neurons of the neocortex, hippocampus, and thalamus in maternal Ube3a knockout mice. We examined the effects of MP-III-022, an α5-containing GABA_A receptor-selective positive allosteric modulator, and gaboxadol, a δ-containing GABA_A receptor agonist, on EEG, seizure threshold, and anxiety-like behavior.

Tonic inhibition was reduced in cortical layer 5 and hippocampal CA1 pyramidal neurons but preserved in thalamic relay neurons. This reduction correlated with elevated GAT1 expression in the cortex and hippocampus but not the thalamus. MP-III-022 reduced abnormal slow-wave EEG activity, increased seizure thresholds, and improved anxiety-like behavior. In contrast, gaboxadol enhanced slow-wave activity and lowered seizure thresholds.

Deficits in tonic inhibition in AS mice are region-specific. These region-dependent differences in tonic inhibition, rather than a global loss, likely underlie EEG abnormalities and heightened seizure susceptibility. α5-containing GABA_A receptors may offer a promising therapeutic target for adjunctive AS treatment.