# Understanding the role of MeCP2 in the cerebellum and the therapeutic potential of extended training in Rett syndrome

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2021 · $40,731

## Abstract

PROJECT SUMMARY/ABSTRACT
Rett syndrome is a devastating childhood neurological disorder that robs young girls of their motor, language,
and social skills. Although the genetic cause of Rett syndrome was discovered two decades ago, the precise
mechanism by which mutations in MECP2 cause Rett syndrome has remained elusive. Such a critical gap in
knowledge has hindered the development of effective treatments. Previous studies have highlighted the
importance of MeCP2 in many brain regions. However, the role of MeCP2 in orchestrating the functions of the
cerebellum remains unknown, despite motor incoordination and ataxia being prominent features in Rett
syndrome. To address this, I studied mice conditionally lacking Mecp2 in the cerebellum and found that they
displayed motor defects that improved with extended training. I used neuroanatomical analysis, in vivo calcium
imaging, and in vivo electrophysiology to explore the underlying network dysfunction in the cerebellum. The
fact that extended training rescued the motor defects raised the exciting possibility that neural circuits affected
by MeCP2 dysfunction are amenable to intervention. I validated this hypothesis by demonstrating that
extended training in symptomatic Mecp2+/- female (Rett) mice, a clinically relevant model of global MeCP2
dysfunction, partially ameliorated their motor impairments. Because the clinical course of Rett syndrome starts
with a period of normal development, I performed motor training beginning in the pre-symptomatic period. To
my surprise, pre-symptomatic training dramatically improved the motor performance of Rett mice. I will build on
these encouraging results and explore the ability of extended training to overcome defects in spatial learning,
another debilitating feature of Rett syndrome. These discoveries will provide mechanistic insights into the origin
of the motor incoordination and ataxia that plagues patients with Rett syndrome, and raise the exciting
possibility that extended training might improve multiple symptoms of the disease. The implications of this
study have therapeutic potential as pre-symptomatic diagnosis and early rehabilitation may be the key to
modifying clinical aspects of Rett syndrome.

## Key facts

- **NIH application ID:** 10218231
- **Project number:** 5F30HD097871-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Nathan Achilly
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,731
- **Award type:** 5
- **Project period:** 2019-07-27 → 2022-05-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218231

## Citation

> US National Institutes of Health, RePORTER application 10218231, Understanding the role of MeCP2 in the cerebellum and the therapeutic potential of extended training in Rett syndrome (5F30HD097871-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218231. Licensed CC0.

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