Binge-like ethanol treatment in adolescence impairs autophagy and hinders synaptic maturation: Role of TLR4.

Adolescence is a developmental period of brain maturation in which remodeling and changes in synaptic plasticity and neural connectivity take place in some brain regions. A different mechanism participates in adolescent brain maturation, including autophagy processes that play a role in synaptic development and plasticity. Alcohol is a neurotoxic compound whose abuse in adolescence causes TLR4 response activation by triggering neuroinflammation, neural damage and behavioral alterations. However, the potential participation of autophagy in long-term neurochemical and cognitive dysfunctions induced by binge ethanol drinking in adolescence is uncertain. We therefore evaluated whether binge ethanol drinking alters autophagy pathways by contributing to adolescent synaptic dysfunctions, and if the immune receptor TLR4 response participates in these events. With wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3.0 g/kg) for 2 weeks, we show that binge-like ethanol exposure in adolescence impairs autophagy machinery by increasing autophagy inhibitor mTOR by lowering LC3-II levels and accumulating p62. Inhibition of mTOR, by rapamycin, restores the levels of excitatory scaffolding synaptic proteins (PSD-95 or SHANK3), p62, and partly reestablishes the LC3-II levels in the prefrontal cortices of ethanol-treated WT mice. Elimination of the TLR4 receptors using TLR4-KO mice prevents autophagy dysfunctions and reduces the number or size of the synaptic connections induced by ethanol. These results suggest the role of autophagy dysfunctions in the structural synaptic plasticity alterations induced by binge alcohol in adolescence, and support the participation of the TLR4 response in these events.