TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment

Brain Behav Immun. 2015 Mar;45:233-44. doi: 10.1016/j.bbi.2014.11.015. Epub 2014 Dec 5.

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.

Keywords: Adolescence; Binge ethanol treatment; Cognitive behavior; Myelin alterations; Synaptic dysfunction; TLR4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol-Related Disorders / genetics*
  • Animals
  • Central Nervous System Depressants / adverse effects
  • Central Nervous System Depressants / pharmacology*
  • Cognition / drug effects*
  • Cognition Disorders / chemically induced
  • Cognition Disorders / genetics*
  • Cyclooxygenase 2 / drug effects
  • Cyclooxygenase 2 / immunology
  • Ethanol / adverse effects
  • Ethanol / pharmacology*
  • HMGB1 Protein / drug effects
  • HMGB1 Protein / immunology
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / drug effects
  • Mitogen-Activated Protein Kinase Kinases / immunology
  • Myelin Proteins / drug effects
  • Myelin Proteins / metabolism
  • Myelin Sheath / drug effects*
  • Myelin Sheath / genetics
  • Myelin Sheath / ultrastructure
  • NF-kappa B / drug effects
  • NF-kappa B / immunology
  • Nitric Oxide Synthase Type II / drug effects
  • Nitric Oxide Synthase Type II / immunology
  • Signal Transduction / drug effects
  • Synapses / drug effects*
  • Synapses / genetics
  • Synapses / ultrastructure
  • Toll-Like Receptor 4 / genetics*

Substances

  • Central Nervous System Depressants
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Myelin Proteins
  • NF-kappa B
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Ethanol
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Mitogen-Activated Protein Kinase Kinases