{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:54:53Z","timestamp":1760144093502,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T00:00:00Z","timestamp":1709683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The L1 cell adhesion molecule (L1) has demonstrated a range of beneficial effects in animal models of spinal cord injury, neurodegenerative disease, and ischemia; however, the role of L1 in TBI has not been fully examined. Mutations in the L1 gene affecting the extracellular domain of this type 1 transmembrane glycoprotein have been identified in patients with L1 syndrome. These patients suffer from hydrocephalus, MASA (mental retardation, adducted thumbs, shuffling gait, aphasia) symptoms, and corpus callosum agenesis. Clinicians have observed that recovery post-traumatic brain injury (TBI) varies among the population. This variability may be explained by the genetic differences present in the general population. In this study, we utilized a novel mouse model of L1 syndrome with a mutation at aspartic acid position 201 in the extracellular domain of L1 (L1-201). We assessed the impact of this specific single nucleotide polymorphism (SNP) localized to the X-chromosome L1 gene on recovery outcomes following TBI by comparing the L1-201 mouse mutants with their wild-type littermates. We demonstrate that male L1-201 mice exhibit significantly worse learning and memory outcomes in the Morris water maze after lateral fluid percussion (LFP) injury compared to male wild-type mice and a trend to worse motor function on the rotarod. However, no significant changes were observed in markers for inflammatory responses or apoptosis after TBI.<\/jats:p>","DOI":"10.3390\/ijms25053043","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T04:03:50Z","timestamp":1709697830000},"page":"3043","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single Nucleotide Polymorphism in Cell Adhesion Molecule L1 Affects Learning and Memory in a Mouse Model of Traumatic Brain Injury"],"prefix":"10.3390","volume":"25","author":[{"given":"Haoyu","family":"Jiang","sequence":"first","affiliation":[{"name":"Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna O.","family":"Giarratana","sequence":"additional","affiliation":[{"name":"Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5555-8501","authenticated-orcid":false,"given":"Thomas","family":"Theis","sequence":"additional","affiliation":[{"name":"Cell Biology and Neuroscience, Rutgers School of Arts and Sciences, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vini","family":"Nagaraj","sequence":"additional","affiliation":[{"name":"Cell Biology and Neuroscience, Rutgers School of Arts and Sciences, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaofeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Smita","family":"Thakker-Varia","sequence":"additional","affiliation":[{"name":"Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melitta","family":"Schachner","sequence":"additional","affiliation":[{"name":"Cell Biology and Neuroscience, Rutgers School of Arts and Sciences, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5694-4946","authenticated-orcid":false,"given":"Janet","family":"Alder","sequence":"additional","affiliation":[{"name":"Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5878","DOI":"10.1038\/s41598-021-85412-1","article-title":"Small compounds mimicking the adhesion molecule L1 improve recovery in a zebrafish demyelination model","volume":"11","author":"Kim","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"458","DOI":"10.3389\/fnins.2020.00458","article-title":"Adhesion Molecule L1 Agonist Mimetics Protect Against the Pesticide Paraquat-Induced Locomotor Deficits and Biochemical Alterations in Zebrafish","volume":"14","author":"Joseph","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41419-021-04348-6","article-title":"A fragment of cell adhesion molecule L1 reduces amyloid-\u03b2 plaques in a mouse model of Alzheimer\u2019s disease","volume":"13","author":"Hu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_4","first-page":"81","article-title":"Cell adhesion molecules of the immunoglobulin superfamily in axonal regeneration and neural repair","volume":"26","author":"Zhang","year":"2008","journal-title":"Restor. Neurol. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s00441-012-1345-4","article-title":"Role of L1CAM for axon sprouting and branching","volume":"349","author":"Frotscher","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"378307","DOI":"10.1155\/2012\/378307","article-title":"Mouse brain PSA-NCAM levels are altered by graded-controlled cortical impact injury","volume":"2012","author":"Budinich","year":"2012","journal-title":"Neural Plast."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1089\/neu.2005.22.978","article-title":"Newly born granule cells in the dentate gyrus rapidly extend axons into the hippocampal CA3 region following experimental brain injury","volume":"22","author":"Emery","year":"2005","journal-title":"J. Neurotrauma"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, H.C., Wang, P.M., Lin, Y.T., Tsai, N.W., Lai, Y.R., Kung, C.T., Su, C.M., and Lu, C.H. (2021). Effects of Hyperbaric Oxygen Therapy on Serum Adhesion Molecules, and Serum Oxidative Stress in Patients with Acute Traumatic Brain Injury. J. Pers. Med., 11.","DOI":"10.3390\/jpm11100985"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13287-015-0268-x","article-title":"PSA-NCAM positive neural progenitors stably expressing BDNF promote functional recovery in a mouse model of spinal cord injury","volume":"7","author":"Zimmermann","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1002\/cne.22588","article-title":"Increase of close homolog of cell adhesion molecule L1 in primary afferent by nerve injury and the contribution to neuropathic pain","volume":"519","author":"Yamanaka","year":"2011","journal-title":"J. Comp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1002\/jnr.22598","article-title":"Increased expression of the close homolog of the adhesion molecule L1 in different cell types over time after rat spinal cord contusion","volume":"89","author":"Wu","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1080\/01616412.2021.1934311","article-title":"Adhesion molecule L1 inhibition increases infarct size in cerebral ischemia-reperfusion without change in blood-brain barrier disruption","volume":"43","author":"Chi","year":"2021","journal-title":"Neurol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2013.07.067","article-title":"Transgenic overexpression of the cell adhesion molecule L1 in neurons facilitates recovery after mouse spinal cord injury","volume":"252","author":"Jakovcevski","year":"2013","journal-title":"Neuroscience"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1089\/089771503322385809","article-title":"Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury","volume":"20","author":"Roonprapunt","year":"2003","journal-title":"J. Neurotrauma"},{"key":"ref_15","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (1993). GeneReviews(\u00ae), University of Washington."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Loers, G., Appel, D., Lutz, D., Congiu, L., Kleene, R., Hermans-Borgmeyer, I., Sch\u00e4fer, M.K.E., and Schachner, M. (2021). Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 35.","DOI":"10.1096\/fj.202002163R"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/978-1-4614-8090-7_9","article-title":"The L1 family of cell adhesion molecules: A sickening number of mutations and protein functions","volume":"8","author":"Hortsch","year":"2014","journal-title":"Adv. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.3389\/fneur.2019.01175","article-title":"BDNF Val66Met Genetic Polymorphism Results in Poor Recovery Following Repeated Mild Traumatic Brain Injury in a Mouse Model and Treatment With AAV-BDNF Improves Outcomes","volume":"10","author":"Giarratana","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19919","DOI":"10.1038\/s41598-020-76849-x","article-title":"APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes","volume":"10","author":"Giarratana","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.bbrc.2022.12.031","article-title":"Effects of L1 adhesion molecule agonistic mimetics on signal transduction in neuronal functions","volume":"642","author":"Nagaraj","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1016\/j.mayocp.2023.02.026","article-title":"Prevalence of and Risk Factors for Post-traumatic Headache in Civilian Patients After Mild Traumatic Brain Injury: A TRACK-TBI Study","volume":"98","author":"Ashina","year":"2023","journal-title":"Mayo Clin. Proc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13054-016-1318-1","article-title":"Chronic impact of traumatic brain injury on outcome and quality of life: A narrative review","volume":"20","author":"Stocchetti","year":"2016","journal-title":"Crit. Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1089\/neu.2021.0062","article-title":"Epidemiology of Chronic Effects of Traumatic Brain Injury","volume":"38","author":"Pugh","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1007\/s11682-012-9197-9","article-title":"Genetic polymorphisms and traumatic brain injury: The contribution of individual differences to recovery","volume":"8","author":"Weaver","year":"2014","journal-title":"Brain Imaging Behav."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.3389\/fneur.2019.01286","article-title":"Genetic Background Influences Acute Response to TBI in Kindling-Susceptible, Kindling-Resistant, and Outbred Rats","volume":"10","author":"Kotloski","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3109\/02699052.2015.1088963","article-title":"Genetic and pharmacological intervention of the p75NTR pathway alters morphological and behavioural recovery following traumatic brain injury in mice","volume":"30","author":"Alder","year":"2016","journal-title":"Brain Inj."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0014-4886(95)90038-1","article-title":"Alternate strategies in lesion-induced reactive synaptogenesis: Differential expression of L1 in two populations of sprouting axons","volume":"131","author":"Styren","year":"1995","journal-title":"Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/cne.903270303","article-title":"Regional distribution of neural cell adhesion molecule (N-CAM) and L1 in human and rodent hippocampus","volume":"327","author":"Miller","year":"1993","journal-title":"J. Comp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3109\/02699052.2011.635362","article-title":"Mild traumatic brain injury (MTBI) leads to spatial learning deficits","volume":"26","author":"Darwish","year":"2012","journal-title":"Brain Inj."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s11910-017-0762-x","article-title":"Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury","volume":"17","author":"Paterno","year":"2017","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1002\/cne.903140207","article-title":"Developmental expression of neural cell adhesion molecules in the mouse neocortex and olfactory bulb","volume":"314","author":"Chung","year":"1991","journal-title":"J. Comp. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1089\/neu.2018.5660","article-title":"Neutralization of Interleukin-1beta following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes","volume":"35","author":"Flygt","year":"2018","journal-title":"J. Neurotrauma"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s12028-016-0290-6","article-title":"Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus","volume":"26","author":"Lim","year":"2017","journal-title":"Neurocrit Care"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1007\/s12031-022-02089-5","article-title":"Honokiol Reduces Mitochondrial Dysfunction and Inhibits Apoptosis of Nerve Cells in Rats with Traumatic Brain Injury by Activating the Mitochondrial Unfolded Protein Response","volume":"72","author":"Sun","year":"2022","journal-title":"J. Mol. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1007\/s11064-016-1997-7","article-title":"Repair of Neurological Function in Response to FK506 Through CaN\/NFATc1 Pathway Following Traumatic Brain Injury in Rats","volume":"41","author":"Wu","year":"2016","journal-title":"Neurochem. Res."},{"key":"ref_36","first-page":"4411","article-title":"Effect of docosahexaenoic acid on traumatic brain injury in rats","volume":"14","author":"Zhu","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3389\/fncel.2019.00166","article-title":"Rapid Changes in Synaptic Strength After Mild Traumatic Brain Injury","volume":"13","author":"Witkowski","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1073\/pnas.2100986118","article-title":"Neurotrophic signaling deficiency exacerbates environmental risks for Alzheimer\u2019s disease pathogenesis","volume":"118","author":"Wu","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1111\/j.1471-4159.2006.04409.x","article-title":"Recognition molecules and neural repair","volume":"101","author":"Loers","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e113962","DOI":"10.15252\/embj.2023113962","article-title":"FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse","volume":"42","author":"Bechara","year":"2023","journal-title":"EMBO J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10634","DOI":"10.1093\/cercor\/bhad311","article-title":"Ankyrin B promotes developmental spine regulation in the mouse prefrontal cortex","volume":"33","author":"Murphy","year":"2023","journal-title":"Cereb. Cortex"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Stoyanova, I.I., and Lutz, D. (2022). Functional Diversity of Neuronal Cell Adhesion and Recognition Molecule L1CAM through Proteolytic Cleavage. Cells, 11.","DOI":"10.3390\/cells11193085"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1002\/glia.22564","article-title":"Olfactory ensheathing cells promote corticospinal axonal outgrowth by a L1 CAM-dependent mechanism","volume":"61","author":"Witheford","year":"2013","journal-title":"Glia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/3043\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:09:54Z","timestamp":1760105394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/5\/3043"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,6]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25053043"],"URL":"https:\/\/doi.org\/10.3390\/ijms25053043","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,3,6]]}}}