Cortical glutamic acid decarboxylase 67 deficiency results in lower cannabinoid 1 receptor messenger RNA expression: Implications for schizophrenia

Stephen M. Eggan, Matthew S. Lazarus, Samuel R. Stoyak, David W. Volk, Jill R. Glausier, Z. Josh Huang, David A. Lewis

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Levels of cannabinoid 1 receptor (CB1R) messenger RNA (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 in schizophrenia, and the magnitude of these differences is strongly correlated with that for glutamic acid decarboxylase 67 (GAD 67) 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, GAD 67, and diacylglycerol lipase alpha (the synthesizing enzyme for the endocannabinoid 2-arachidonoylglycerol) mRNA levels in the medial prefrontal cortex of genetically engineered GAD 67 heterozygous (GAD 67 +/-), CB1R heterozygous (CB1R +/-), CB1R knockout (CB1R -/-), and matched wild-type mice. In GAD 67 +/- mice, GAD 67 and CB1R mRNA levels were significantly reduced by 37% and 16%, respectively, relative to wild-type mice and were significantly correlated across animals (r =.61; p =.01). In contrast, GAD 67 mRNA levels were unaltered in CB1R +/- andCB1R -/- mice. Expression of diacylglycerol lipase alpha mRNA, which is not altered in schizophrenia, was also not altered in any of the genetically engineered mice. The findings that reduced GAD 67 mRNA expression can induce lower CB1R mRNA expression support the hypothesis that lower cortical levels of CB1Rs in schizophrenia may partially compensate for deficient GAD 67-mediated GABA synthesis by reducing endogenous cannabinoid suppression of GABA release.

Original languageEnglish (US)
Pages (from-to)114-119
Number of pages6
JournalBiological Psychiatry
Volume71
Issue number2
DOIs
StatePublished - Jan 15 2012
Externally publishedYes

Keywords

  • Cannabis
  • GABA
  • cholecystokinin
  • cognition
  • in situ hybridization
  • interneurons
  • mouse model
  • working memory

ASJC Scopus subject areas

  • Biological Psychiatry

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