Cortical glutamic acid decarboxylase 67 deficiency results in lower cannabinoid 1 receptor messenger RNA expression: implications for schizophrenia.
- Authors
- Eggan, Stephen M; Lazarus, Matthew S; Stoyak, Samuel R; Volk, David W; Glausier, Jill R; Huang, Z Josh; Lewis, David A
- Year
- 2012
- Journal
- Biological psychiatry
- PMID
- 22036037
- DOI
- 10.1016/j.biopsych.2011.09.014
- PMCID
- PMC3237751
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Transcript levels in the mPFC of adult wild-type and GAD67+/− mice. Representative film autoradiograms illustrating the expression of GAD67 (A, B), CB1R (D, E), and DAGLα (G, H) mRNAs. The density of hybridization signal for each transcript is presented in pseudocolor according to the calibration bars below B, E, and H. Expression of GAD67 and CB1R mRNA in GAD67+/− mice (B, E) appears lower than in wild-type mice (A, D), whereas DAGLα (G, H) does not appear to differ across the two conditions. Note that CB1R mRNA signal is most pronounced in the superficial cortical layers, consistent with the laminar distribution of CCK-containing GABA neurons that heavily express CB1R mRNA and that are the principal CB1R mRNA expressing neuron type in the cortex(4). White contours denote the quantified region of the mPFC. Comparison of cortical GAD67 (C), CB1R (F), and DAGLα (I) mRNA levels by film optical density (OD) in wild-type (diamonds) and GAD67+/− (triangles) mice. Mean values for each genetic condition are indicated by hash marks. Scale bar (1mm) in H applies to all panels.
Positive correlation between levels of CB1R and GAD67 mRNAs in adult wild-type and GAD67+/− mice. These findings suggest that changes in CB1R mRNA expression parallel changes in GAD67 mRNA expression.
Cellular expression of CB1R mRNA. Representative photomicrograph of Nissl-counterstained, emulsion-exposed tissue section showing silver grains representing CB1R mRNA clustered over a subset of neuronal cell bodies (A). Scale bar = 30 μm. Expression of CB1R mRNA is lower in GAD67+/− mice relative to wild-type mice (B).
Transcript levels in the mPFC of adult wild-type, CB1R+/−, and CB1R−/− mice. Representative film autoradiograms illustrating the expression of CB1R (A, B, C), GAD67 (E, F, G), and DAGLα (I, J, K) mRNA. The density of hybridization signal for each transcript is presented in pseudocolor according to the calibration bars below C, G, and K. Expression of CB1R mRNA is markedly reduced in CB1R+/− mice (B) and nearly undetectable in CB1R−/− mice (C) compared to wild-type mice (A). Expression of GAD67 (E, F, G) and DAGLα (I, J, K) mRNA appear unaltered in either genetic condition compared to wild-type mice. White contours denote the quantified region of the mPFC. Comparison of cortical CB1R (D), GAD67 (H), and DAGLα (L) mRNA levels by film optical density (OD) in wild-type (diamonds), CB1R+/− (triangles), and CB1R−/− (circles) mice. Mean values for each condition are indicated by hash marks. Scale bar (1mm) in K applies to all panels.
| Name | Type |
|---|---|
| 2-AG | drug |
| 35S-CTP local | drug |
| BioMaxMR film local | drug |
| C57BL/6J | cohort |
| carbon-14 local | drug |
| CB1R+/− local | variant |
| CB1R−/− local | variant |
| CB1 receptor | drug |
| CB1R+/− mice local | cohort |
| CB1R−/− mice local | cohort |
| CB1R mRNA expression local | phenotype |
| CB1R mRNA levels local | phenotype |
| Cck | gene |
| cingulate cortex | anatomy |
| Cnr1 | gene |
| CNR1+/− mice local | cohort |
| CNR1−/− mice local | cohort |
| cortex | anatomy |
| cortical mantle | anatomy |
| Cresyl violet | drug |
| D-19 local | drug |
| DAGLA | drug |
| DAGLα | gene |
| dlPFC | anatomy |
| dorsolateral prefrontal cortex | anatomy |
| FLP recombinase | drug |
| GABA | phenotype |
| GAD1 | gene |
| Gad1lox/+ local | cohort |
| Gad1lox/lox local | cohort |
| GAD1+/− mice local | cohort |
| GAD67+/− local | cohort |
| GAD67+/− local | variant |
| GAD67 heterozygous mice local | cohort |
| GAD67+/- mice local | cohort |
| GAD67+/− mice local | cohort |
| GAD67 mRNA levels local | phenotype |
| GAD67 WT mice local | cohort |
| grain density measures local | phenotype |
| layer 6 local | anatomy |
| medial prefrontal cortex | anatomy |
| mice | cohort |
| motor areas | anatomy |
| mouse brain | anatomy |
| Mox2-Cre local | cohort |
| mPFC | anatomy |
| MPI2 embryonic stem cells local | cohort |
| normal phenotype local | phenotype |
| NTB2 emulsion local | drug |
| OD measures local | phenotype |
| perinatal lethality | phenotype |
| PFC | anatomy |
| PGK-neo local | drug |
| pial surface | anatomy |
| prefrontal cortex | anatomy |
| prelimbic cortex | anatomy |
| schizophrenia | phenotype |
| SP6 RNA polymerase local | drug |
| Subjects with schizophrenia local | cohort |
| supplementary motor area | anatomy |
| SupraFrost slides local | drug |
| T7 RNA polymerase local | drug |
| white matter | anatomy |
| Wild-type local | variant |
| wild-type mice | cohort |
| working memory | phenotype |
| WT | cohort |
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