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

Shen, J.; Shen, P.; Goncalez, J.; Jackson, M.; Polepalli, L.; Dheeravath, K.; Li, T.; Hamki, A.; Hamki, M.; Hicks, C.; Li, C.; Pozzo-Miller, L.; Li, W.

2026-05-26 neuroscience
10.64898/2026.05.25.727684 bioRxiv
Show 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.

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