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ACh is packaged into synaptic vesicles by the vesicular ACh transporter (VAChT), and disruptions in its release can impair muscle contraction, as seen in congenital myasthenic syndromes (CMS). Recently, <jats:italic>VAChT<\/jats:italic> gene mutations were identified in humans displaying varying degrees of myasthenia. Moreover, mice with a global deficiency in VAChT expression display several characteristics of CMS. Despite these findings, little is known about how a long\u2010term decrease in VAChT expression <jats:italic>in\u00a0vivo<\/jats:italic> affects MNs structure and function. Using Cre\u2010loxP technology, we generated a mouse model where VAChT is deleted in select groups of MNs (mnVAChT\u2010KD). Molecular analysis revealed that the VAChT deletion was specific to MNs and affected approximately 50% of its population in the brainstem and spinal cord, with alpha\u2010MNs primarily targeted (70% in spinal cord). Within each animal, the cell body area of VAChT\u2010deleted MNs was significantly smaller compared to MNs with VAChT preserved. Likewise, muscles innervated by VAChT\u2010deleted MNs showed atrophy while muscles innervated by VAChT\u2010containing neurons appeared normal. In addition, mnVAChT KD mice had decreased muscle strength, were hypoactive, leaner and exhibited kyphosis. This neuromuscular dysfunction was evident at 2\u00a0months of age and became progressively worse by 6\u00a0months. Treatment of mutants with a cholinesterase inhibitor was able to improve some of the motor deficits. As these observations mimic what is seen in CMS, this new line could be valuable for assessing the efficacy of potential CMS drugs.<\/jats:p>","DOI":"10.1111\/febs.15825","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T19:50:50Z","timestamp":1616010650000},"page":"5331-5349","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Motoneuron\u2010specific loss of VAChT mimics neuromuscular defects seen in congenital myasthenic syndrome"],"prefix":"10.1111","volume":"288","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5788-6223","authenticated-orcid":false,"given":"Julliane V.","family":"Joviano\u2010Santos","sequence":"first","affiliation":[{"name":"Robarts Research Institute Schulich School of Medicine &amp; Dentistry University of Western Ontario London Canada"},{"name":"Departamento de Morfologia Instituto de Ci\u00eancias Biol\u00f3gicas Universidade Federal de Minas Gerais Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornela","family":"Kljakic","sequence":"additional","affiliation":[{"name":"Robarts Research Institute Schulich School of Medicine &amp; Dentistry University of Western Ontario London Canada"},{"name":"Department of Anatomy and Cell Biology Schulich School of Medicine &amp; Dentistry University of Western Ontario London Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5829-1141","authenticated-orcid":false,"given":"Matheus P. 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