HDAC inhibitor ameliorates behavioral deficits in Mecp2308/y mouse model of Rett syndrome

Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder. More than 95% of classic RETT syndrome cases result from pathogenic variants in the methyl-CpG binding protein 2 (MECP2) gene. Nevertheless, it has been established that a spectrum of neuropsychiatric phenotypes is associated with MECP2 variants in both females and males. We previously reported that microtubule growth velocity and vesicle transport directionality are altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared to that of their wild-type littermates suggesting deficit in microtubule dynamics. In this study, we report that administration of tubastatin A, a selective HDAC6 inhibitor, restored microtubule dynamics in Mecp2-deficient astrocytes. We furthermore report that daily doses of tubastatin A reversed early impaired exploratory behavior in male Mecp2(308/y) mice. These findings are a first step toward the validation of a novel treatment for RTT.

Automated summary

Rett syndrome is a rare neurodevelopmental disorder, with more than 95% of cases linked to variants in the MECP2 gene. By modulating microtubule dynamics, the selective HDAC6 inhibitor tubastatin A can reverse exploratory behavior deficits associated with Rett syndrome.