title: TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment.
abstract: The adolescent brain undergoes important dynamic and plastic cell changes, including overproduction of axons and synapses, followed by rapid pruning along with ongoing axon myelination. These developmental changes make the adolescent brain particularly vulnerable to neurotoxic and behavioral effects of alcohol. Although the mechanisms of these effects are largely unknown, we demonstrated that ethanol by activating innate immune receptors toll-like receptor 4 (TLR4), induces neuroinflammation and brain damage in adult mice. The present study aims to evaluate whether intermittent ethanol treatment in adolescence promotes TLR4-dependent pro-inflammatory processes, leading to myelin and synaptic dysfunctions, and long-term cognitive impairments. Using wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3.0g/kg) for 2weeks, we show that binge-like ethanol treatment activates TLR4 signaling pathways (MAPK, NFκB) leading to the up-regulation of cytokines and pro-inflammatory mediators (COX-2, iNOS, HMGB1), impairing synaptic and myelin protein levels and causing ultrastructural alterations. These changes were associated with long-lasting cognitive dysfunctions in young adult mice, as demonstrated with the object recognition, passive avoidance and olfactory behavior tests. Notably, elimination of TLR4 receptors prevented neuroinflammation along with synaptic and myelin derangements, as well as long-term cognitive alterations. These results support the role of the neuroimmune response and TLR4 signaling in the neurotoxic and behavioral effects of ethanol in adolescence.
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Montesinos
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pascual
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Pla
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Maldonado
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Rodríguez-Arias
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Miñarro
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/Eduardo Primo Yúfera, 3, 46012 Valencia, Spain. Electronic address: cguerri@cipf.es.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Guerri
mesh_terms: D019973:Alcohol-Related Disorders / Q000235:genetics*; D000818:Animals; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000276:immunology; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000276:immunology; D009185:Myelin Proteins / Q000187:drug effects / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D002492:Central Nervous System Depressants; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D009185:Myelin Proteins; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Adolescence; Binge ethanol treatment; Cognitive behavior; Myelin alterations; Synaptic dysfunction; TLR4