Figure 7.

Schematic diagram showing the molecular mechanism by which CB1R-mediated activation of caspase-3 degrades MeCP2, leading to neurobehavioral abnormalities in postnatal ethanol-exposed mice. It was revealed previously that P7 ethanol treatment activates CB1R and inhibits pCREB and Arc expression, leading to neurodegeneration in neonatal mice and persistent neurobehavioral abnormalities in adult mice (Subbanna et al., 2015a). Here, we show that inhibition of CB1R (Subbanna et al., 2013a, 2014) or caspase-3 prevents loss of MeCP2 and rescues pCREB/Arc defects in neonatal mice. Inhibition of caspase-3 in P7 mice also protected against the synaptic plasticity, Arc expression, activity-dependent signaling and behavioral defects in adult mice exposed to ethanol at P7. These observations suggest that CB1R (Subbanna et al., 2013a, 2014)/caspase-3-mediated MeCP2 loss in early development causes neurobehavioral abnormalities in postnatal ethanol-exposed adult mice (↓, ethanol effects; ⊥, drug effects).