Deleting <i>Mecp2</i> from the cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice.

Abstract

Rett syndrome is a devastating childhood neurological disorder caused by mutations in <i>MECP2</i>. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting <i>Mecp2</i> from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. Little is known about the function of <i>Mecp2</i> in the cerebellum, a brain region critical for motor function. Here we show that deleting <i>Mecp2</i> from the cerebellum, but not from its neuronal subtypes, causes a delay in motor learning that is overcome by additional training. We observed irregular firing rates of Purkinje cells and altered heterochromatin architecture within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.