RO4938581, a GABAA-α5 negative allosteric modulator rescued behavioral and EEG phenotypes of a mouse model of Dup15q syndrome

We investigated the correlation between increased gene copy number of gamma aminobutyric acid type A (GABA_A) receptor α5-containing subunits and electrophysiological and behavioral phenotypes in a mouse model of Dup15q syndrome (15q dup) and tested the hypothesis that selectively inhibiting the activity of GABA_A-α5 receptors may have therapeutic effects. Dup15q syndrome is a rare neurodevelopmental disorder caused by copy number gains of the 15q11.2-q13.1 chromosomal region, which includes UBE3A and a cluster of three genes (GABRA5, GABRB3, and GABRG3) encoding GABA_A receptor subunits, all of which are critical for neural development and function. Most affected children display hypotonia, motor delays, intellectual disability, and epilepsy, as well as a characteristic electroencephalography (EEG) beta-band phenotype. There is no disease-modifying therapy available. Autoradiography showed increased density of GABA_A-α5 receptors in the brains of 15q dup mice, while electrophysiology revealed enhanced GABAergic transmission in hippocampal slices from these mice. A GABA_A-α5 negative allosteric modulator, RO4938581, decreased inhibitory synaptic charge transfer in 15q dup hippocampal slices. The behavioral analyses confirmed inflexibility in learning and abnormal social behaviors in 15q dup mice, and both phenotypes were normalized following chronic treatment with RO4938581. EEG recordings showed increased beta-power in 15q dup mice - which resembled the spectral signature of subjects with Dup15q - and was partially normalized following RO4938581 treatment. Our results suggest that excessive expression and function of the GABA_A-α5 receptor subtype plays a key role in the pathophysiology of Dup15q and GABA_A-α5 NAMs may represent a potential precision medicine therapeutic option.