ROLE OF THE TLR4 IMMUNE response in ethanol-induced neurodevelopmental alterations IN FETAL ALCOHOL SPECTRUM DISORDERS

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Guerri C., Montesinos J., Pascual M.

Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, Valencia, Spain.

Inflammation during brain development participates in the pathogenesis of early brain injury and cognitive dysfunctions. Alcohol drinking is associated with elevated maternal blood cytokines/chemokines, which can be transferred to the fetus and can induce dysregulation of the immune response to affect the developing brain. We have shown that ethanol by activating the toll-like (TLR4) immune receptors, causes neuroinflammation, myelin dysfunction, brain damage and cognitive effects in adults and adolescents. However, it is presently unknown the potential role of the neuroimmune-TLR4 response in the pathogenesis of fetal-alcohol-spectrum-disorders (FASD). We evaluate the hypothesis that “alcohol, by activating TLR4 response, increases inflammatory mediators in serum and brain of both alcohol-drinking mother and foetus affecting neurogenesis and neuronal myelin architecture in the developing brain”. We use C57BL/6 WT and TLR4 knockout (KO) female mice treated with alcohol during gestation and lactation. We show that the levels of some cytokines (IL-1β, IL-17) and chemokines (MCP-1, MIP-1α, fractalkine) were up-regulated in serum and in the cortex of alcohol-treated WT pregnant female dams and also in the cortex of their newborn offspring. These events were associated with the activation of microglia, as shown by the CD11b and MHCII, and with a reduction in the neuronal marker Tuj-1 and in the synaptic (synaptotagmin, synapsin IIa) and myelin (MBP, PLP) proteins in 0-, 20- and 66-day-old WT pups exposed prenatally and postnatally to ethanol. These changes were related with cortical ultrastructural alterations of myelin and synaptic structures in 20-day-old WT pups exposed to ethanol. Furthermore, 66-day-old WT pups exposed prenatally and postnatally to alcohol showed behavioral impairments in the elevated plus maze and passive avoidance. Notably, elimination of the TLR4, by using TLR4-KO mice, abolishes the up-regulation of cytokines/chemokines in both alcohol-treated dams and their offspring, and also eliminates alcohol-induced neuronal and glial dysfunctions in the postnatal pups. These results suggest that the activation of the immune response and TLR4 system might underlie some neurodevelopmental defects in FASD. (Supported by PNSD2014, ERAB, ACOM 2014, SAF2015- SAF2015-6917).