MeCP2 is Necessary in Cerebellar Purkinje Cells for Precise Network Dynamics During Associative Motor Learning

Abstract Loss-of-function variants of MECP2 cause Rett syndrome; however, their impact on cerebellar computations for learning remains poorly understood. Here, we show that Mecp2 deletion specifically in Purkinje cells does not broadly disrupt cerebellar-dependent behaviors but selectively compromises those that require precise timing, coordination, and associative updating in the cerebellar cortex. Mecp2 loss altered the emergence of learning-related Purkinje cell activity in vivo and disrupted their intrinsic and synaptic properties that support adaptive cerebellar output. These findings identify MeCP2 as a critical player in Purkinje cell function to regulate cerebellar learning signals and suggest that Rett syndrome-related motor dysfunction reflects impaired adaptive computation rather than a generalized loss of motor capacity.