Because CB1R activation suppresses GABA neurotransmission (8), we previously suggested that a lower density of CB1Rs in schizophrenia could be a cell type-specific, homeostatic adaptation to partially compensate for upstream reductions in GAD67-mediated GABA synthesis in CB1R/CCK-containing neurons (5,6). That is, a down-regulation of CB1Rs could reduce the endocanabinoid-mediated block of GABA release from the terminals of CB1R/CCK-containing neurons, thereby enhancing GABA neurotransmission in cells with deficient GABA synthesis (5,6). As a proof-of-concept test of this hypothesis, we assessed GAD67 and CB1R mRNA levels in the medial prefrontal cortex of genetically-engineered GAD67 heterozygous (GAD67+/−), CB1R heterozygous (CB1R+/−), CB1R knockout (CB1R−/−), and matched wild-type (WT) mice. In addition, to test the specificity of the causal relationship between reduced GAD67 mRNA and lower CB1R mRNA levels, we also assessed mRNA levels for diacylglycerol lipase alpha (DAGLα), the synthesizing enzyme for 2-arachidonoylglycerol (2-AG) (the principal endocannabinoid in the DLPFC), which are unaltered in schizophrenia (9).
