2. Academic Validation
  3. Purkinje-cell-specific MeCP2 deficiency leads to motor deficits and autistic-like behavior due to aberrations in PTP1B-TrkB-SK signaling

Purkinje-cell-specific MeCP2 deficiency leads to motor deficits and autistic-like behavior due to aberrations in PTP1B-TrkB-SK signaling

  • Cell Rep. 2023 Dec 13;42(12):113559. doi: 10.1016/j.celrep.2023.113559.
Fang-Xiao Xu 1,  Xin-Tai Wang 2,  Xin-Yu Cai 1,  Jia-Yu Liu 1,  Jing-Wen Guo 1,  Fan Yang 3,  Wei Chen 1,  Martijn Schonewille 4,  Chris De Zeeuw 5,  Lin Zhou 6,  Ying Shen 7
Affiliations

Affiliations

  • 1 Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
  • 2 Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China.
  • 3 Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Department of Neuroscience, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands.
  • 5 Department of Neuroscience, Erasmus University Medical Center, 3000 DR Rotterdam, the Netherlands; The Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Science, 1105 CA Amsterdam, the Netherlands. Electronic address: [email protected].
  • 6 Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China. Electronic address: [email protected].
  • 7 Department of Physiology and Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; International Institutes of Medicine, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China; Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310000, China. Electronic address: [email protected].
PMID: 38100348 DOI: 10.1016/j.celrep.2023.113559
Abstract

Patients with Rett syndrome suffer from a loss-of-function mutation of the Mecp2 gene, which results in various symptoms including autistic traits and motor deficits. Deletion of Mecp2 in the brain mimics part of these symptoms, but the specific function of methyl-CpG-binding protein 2 (MeCP2) in the cerebellum remains to be elucidated. Here, we demonstrate that Mecp2 deletion in Purkinje cells (PCs) reduces their intrinsic excitability through a signaling pathway comprising the small-conductance calcium-activated Potassium Channel PTP1B and TrkB, the receptor of brain-derived neurotrophic factor. Aberration of this cascade, in turn, leads to autistic-like behaviors as well as reduced vestibulocerebellar motor learning. Interestingly, increasing activity of TrkB in PCs is sufficient to rescue PC dysfunction and abnormal motor and non-motor behaviors caused by Mecp2 deficiency. Our findings highlight how PC dysfunction may contribute to Rett syndrome, providing insight into the underlying mechanism and paving the way for rational therapeutic designs.

Keywords

CP: Neuroscience; Rett syndrome; TrkB; cerebellum; compensatory eye movements; social interaction.

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