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Numerous gene mutations in the L1 cell adhesion molecule (L1CAM, hereafter abbreviated L1) were identified in L1 syndrome patients, and those affecting the extracellular domain of this transmembrane type 1 glycoprotein show the most severe phenotypes. Previously analyzed rodent models of the L1 syndrome focused on L1\u2010deficient animals or mouse mutants with abrogated cell surface expression of L1, making it difficult to test L1 function\u2010triggering mimetic compounds with potential therapeutic value. To overcome this impasse, we generated a novel L1 syndrome mouse with a mutation of aspartic acid at position 201 in the extracellular part of L1 (p.D201N, hereafter termed L1\u2010201) that displays a cell surface\u2010exposed L1 accessible to the L1 mimetics. Behavioral assessment revealed an increased neurological deficit score and increased locomotor activity in male L1\u2010201 mice carrying the mutation on the X\u2010chromosome. Histological analyses of L1\u2010201 mice showed features of the L1 syndrome, including enlarged ventricles and reduced size of the corpus callosum. Expression levels of L1\u2010201 protein as well as extent of cell surface biotinylation and immunofluorescence labelling of cultured cerebellar neurons were normal. Importantly, treatment of these cultures with the L1 mimetic compounds duloxetine, crotamiton, and trimebutine rescued impaired cell migration and survival as well as neuritogenesis. Altogether, the novel L1 syndrome mouse model provides a first experimental proof\u2010of\u2010principle for the potential therapeutic value of L1 mimetic compounds.<\/jats:p>","DOI":"10.1096\/fj.202002163r","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T06:37:43Z","timestamp":1611383863000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics"],"prefix":"10.1096","volume":"35","author":[{"given":"Gabriele","family":"Loers","sequence":"first","affiliation":[{"name":"Zentrum f\u00fcr Molekulare Neurobiologie Universit\u00e4tsklinikum Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Appel","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology University Medical Center of the Johannes Gutenberg\u2010University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lutz","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Molekulare Neurobiologie Universit\u00e4tsklinikum Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovica","family":"Congiu","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Molekulare Neurobiologie Universit\u00e4tsklinikum Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5935-5266","authenticated-orcid":false,"given":"Ralf","family":"Kleene","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Molekulare Neurobiologie Universit\u00e4tsklinikum Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irm","family":"Hermans\u2010Borgmeyer","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Molekulare Neurobiologie Universit\u00e4tsklinikum Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K. 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