The mechanism through which deficient GAD67 expression results in reduced CB1R expression in the GAD67+/− mice remains to be determined. Lower GAD67 expression could cause alterations in cortical circuitry that produce increased 2-AG levels and subsequently CB1R down-regulation. However, the expression of DAGLα mRNA, which synthesizes 2-AG in pyramidal neurons postsynaptic to CB1R/CCK-containing axon terminals, was not altered in GAD67+/− mice. Alternatively, the effect of decreased GAD67 expression on CB1R expression may occur through a cell autonomous mechanism within CB1R/CCK-containing GABA neurons. Consistent with this idea, DAGLα mRNA expression was not altered in CB1R−/− mice suggesting that alterations in CB1R expression can occur independently of, and without alterations in, other components of the endocannabinoid system. Alternatively, because GAD67 is critical for the development of perisomatic axon terminals (10), deficient GAD67 expression may result in fewer CB1R-containing axon terminals and thus a reduced need for CB1R mRNA expression.
