Cortical Glutamic Acid Decarboxylase 67 Deficiency Results in Lower Cannabinoid 1 Receptor Messenger RNA Expression: Implications for Schizophrenia

Abstract

Background Levels of cannabinoid 1 receptor (CB1R) mRNA and protein, which are expressed most heavily in the cholecystokinin class of 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. Methods 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. Results In GAD67+/− mice, GAD67 and CB1R mRNA levels were significantly reduced by 37% and 16%, respectively, relative to wild-type mice 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. Conclusions 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.

Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks

“…Many previous studies 7,8,45,46 have focused on the relationship between CAD and SCZ, whereas the correlation between CAD and MDD has received much less attention. Although depressive disorders are highly comorbid with CAD in clinical settings, 47 to our knowledge no previous genomics study has explored CAD-MDD pleiotropy.…”

Disrupting the clustering of GABAAreceptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits

“…In tissue sections from human subjects with schizophrenia a variety of GABA-related deficits have been observed. Specifically, studies of frontal cortex tissue have shown reductions in GAT-1 (30) and GABA A R α1 mRNA expression and reduced density of ankyrin-G immunoreactivty (31) along with an increase in α2 expression (32) along axon-initial segments, as well as deficits in transcripts encoding CCK (33) and cannabinoid 1 receptor (34).…”

Development of Cortical Interneurons

“…In the first stage, LCN attains their mature fates, defined by their distinctive connectivities, neurochemistries, and firing properties, which culminate in their attaining distinct functions within juvenile cortical circuits (Ascoli et al, 2008). A detailed discussion of this process is beyond the scope of this review, but interacting influences of transcription factors (Close et al, 2012;Cobos et al, 2005), neurotransmitters (Eggan et al, 2012), neurotrophins (Huang et al, 1999), cell adhesion molecules (Pillai-Nair et al, 2005), and their activities are clearly in play (Bartolini et al, 2013;Batista-Brito and Fishell, 2009). The second stage of LCN maturation occurs in concert with cortical circuitry maturation, a process that begins in the early postnatal time period but is not finally achieved in all cortical regions until adolescence or young adulthood.…”