CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol.

Fetal alcohol spectrum disorders (FASD) represent a wide array of defects that arise from ethanol exposure during development. However, the underlying molecular mechanisms are limited. In the current report, we aimed to further evaluate the cannabinoid receptor type 1 (CB1R)-mediated mechanisms in a postnatal ethanol-exposed animal model. We report that the exposure of postnatal day 7 (P7) mice to ethanol generates p25, a CDK5-activating peptide, in a time- and CB1R-dependent manner in the hippocampus and neocortex brain regions. Pharmacological inhibition of CDK5 activity before ethanol exposure prevented accumulation of cleaved caspase-3 (CC3) and hyperphosphorylated tau (PHF1) (a marker for neurodegeneration) in neonatal mice and reversed cAMP response element-binding protein (CREB) activation and activity-regulated cytoskeleton-associated protein (Arc) expression. We also found that postnatal ethanol exposure caused a loss of RhoGTPase-related, Rac1, gene expression in a CB1R and CDK5 activity-dependent manner, which persisted to adulthood. Our epigenetic analysis of the Rac1 gene promoter suggested that persistent suppression of Rac1 expression is mediated by enhanced histone H3 lysine 9 dimethylation (H3K9me2), a repressive chromatin state, via G9a recruitment. The inhibition of CDK5/p25 activity before postnatal ethanol exposure rescued CREB activation, Arc, chromatin remodeling and Rac1 expression, spatial memory, and long-term potentiation (LTP) abnormalities in adult mice. Together, these findings propose that the postnatal ethanol-induced CB1R-mediated activation of CDK5 suppresses Arc and Rac1 expression in the mouse brain and is responsible for persistent synaptic plasticity and learning and memory defects in adult mice. This CB1R-mediated activation of CDK5 signaling during active synaptic development may slow down the maturation of synaptic circuits and may cause neurobehavioral defects, as found in this FASD animal model.