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

Nathan P Achilly,Javier F Medina,Olivia A Kim,Ling-Jie He,Huda Y Zoghbi,Gregory J Wojaczynski,Shogo Ohmae,Tao Lin,Roy V Sillitoe

doi:10.7554/elife.64833

Nathan P Achilly, Javier F Medina + Show 7 more

Open Access

https://doi.org/10.7554/elife.64833

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Abstract

Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 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 Mecp2 in the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 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.

Highlights

Loss-of-function mutations in MECP2 cause a severe childhood disorder called Rett syndrome (Amir et al, 1999)
Deleting Mecp2 from all major neuronal subtypes in the cerebellum causes a delay in motor learning
These results demonstrate that deleting Mecp2 from the major cell types in the cerebellum causes a delay in motor learning

Summary

Introduction

Loss-of-function mutations in MECP2 (human gene) cause a severe childhood disorder called Rett syndrome (Amir et al, 1999). The cerebellum contains approximately 75% of all neurons in the brain (Lange, 1975; Sarko et al, 2009) and integrates sensory inputs in order to fine-tune motor output (Manto et al, 2012) This function is critical for motor coordination and motor learning as impairments in the cerebellar circuitry cause ataxia, dystonia, and tremor (White et al, 2016; Bostan and Strick, 2018; Darmohray et al, 2019; Machado et al, 2020). We deleted Mecp from the cerebellum and discovered that cerebellar knockout (KO) animals had deficits in motor learning that were overcome with additional training This motor learning delay was accompanied by irregular firing patterns of Purkinje cells and a reduction in H3K9me levels in heterochromatic foci of granule cells, Purkinje cells, and molecular layer interneurons. These data indicate that Mecp deficiency in the cerebellum is consequential and contributes to the motor dysfunction seen in Rett syndrome

Results

Discussion

Materials and methods