|Levels of cannabinoid 1 receptor (CB1R) mRNA and protein, which are expressed most heavily in the cholecystokinin class of γ-aminobutyric acid (GABA) neurons, are lower in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia, and the magnitude of these differences is strongly correlated with that for glutamic acid decarboxylase (GAD67) mRNA, a synthesizing enzyme for GABA. However, whether this correlation reflects a cause-effect relationship is unknown. Using quantitative in situ hybridization, we measured CB1R, GAD67, and diacylglycerol lipase alpha (DAGLα; the synthesizing enzyme for the endocannabinoid 2-arachidonoylglycerol) mRNA levels in the medial prefrontal cortex of genetically-engineered GAD67 heterozygous (GAD67+/-), CB1R heterozygous (CB1R+/-), CB1R knockout (CB1R-/-), and matched wild-type mice. In GAD67+/- mice, GAD67 and CB1R mRNA levels were significantly reduced by 37% and 16%, respectively, relative to wild-type mice (see Figure) and were significantly correlated across animals (r=0.61; p=0.01). In contrast, GAD67 mRNA levels were unaltered in CB1R+/- and CB1R-/- mice. Expression of DAGLα mRNA, which is not altered in schizophrenia, was also not altered in any of the genetically-engineered mice. The findings that reduced GAD67 mRNA expression can induce lower CB1R mRNA expression support the hypothesis that lower cortical levels of CB1Rs in schizophrenia may partially compensate for deficient GAD67-mediated GABA synthesis by reducing endogenous cannabinoid suppression of GABA release.
|Eggan SM, Lazarus MS, Stoyak SR, Volk DW, Glausier JR, Huang J, Lewis DA: Cortical GAD67 deficiency results in lower cannabinoid 1 receptor mRNA expression: Implications for schizophrenia. Biol Psychiatry 71:114-119, 2012.