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The loss of motor function is an important clinical feature of RTT that manifests early during the course of the disease. RTT mouse models with mutations in the murine orthologous <jats:italic>Mecp2<\/jats:italic> gene replicate many human phenotypes, including progressive motor impairments. However, relatively little is known about the changes in circuit function during the progression of motor deficit in this model. As the motor cortex is the key node in the motor system for the control of voluntary movement, we measured firing activity in populations of motor cortical neurons during locomotion on a motorized wheel-treadmill. Different populations of neurons intermingled in the motor cortex signal different aspects of the locomotor state of the animal. The proportion of running selective neurons whose activity positively correlates with locomotion speed gradually decreases with weekly training in wild-type mice, but not in <jats:italic>Mecp2<\/jats:italic>-null mice. The fraction of rest-selective neurons whose activity negatively correlates with locomotion speed does not change with training in wild-type mice, but is higher and increases with the progression of locomotion deficit in mutant mice. The synchronization of population activity that occurs in WT mice with training did not occur in <jats:italic>Mecp2<\/jats:italic>-null mice, a phenotype most clear during locomotion and observable across all functional cell types. Our results could represent circuit-level biomarkers for motor regression in Rett syndrome.<\/jats:p>","DOI":"10.1186\/s13041-022-00965-0","type":"journal-article","created":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T14:02:59Z","timestamp":1662386579000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["MeCP2 deficiency impairs motor cortical circuit flexibility associated with motor learning"],"prefix":"10.1186","volume":"15","author":[{"given":"Yuanlei","family":"Yue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan T.","family":"Ash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Boyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kinter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yipeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2336-2170","authenticated-orcid":false,"given":"Hui","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,5]]},"reference":[{"key":"965_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.10.001","author":"M Chahrour","year":"2007","unstructured":"Chahrour M, Zoghbi HY. 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