Despite heightened sensitivity to cannabis, mice carrying a schizophrenia risk gene (Nrg1) showed normal developmental patterns of key endocannabinoid system molecules, suggesting other mechanisms explain their cannabis vulnerability.
Read this if you are interested in the biological mechanisms connecting genetics, brain development, and cannabis sensitivity.
Endocannabinoid markers peaked at PND 21-35 but showed no difference in at-risk mice
What the researchers found
Researchers tracked the development of the endocannabinoid system across eight time points from birth to adulthood in mice carrying a mutation in neuregulin 1 (Nrg1), a known schizophrenia risk gene. These mutant mice are known to have exaggerated responses to cannabis exposure.
The study mapped the developmental trajectory of four key endocannabinoid system components: CB1 receptors and three enzymes involved in producing and breaking down the endocannabinoid 2-AG. In normal mice, these markers showed dynamic developmental changes, with synthesis and breakdown enzymes peaking around postnatal days 21-35 before declining and stabilizing. Hippocampal CB1 receptor expression peaked at day 21 and then decreased.
Surprisingly, despite the Nrg1 mutant mice's known heightened cannabis sensitivity, none of the endocannabinoid system markers differed between mutant and control mice at any developmental time point. This suggests that the increased cannabis vulnerability in these genetically at-risk mice is not due to differences in the endocannabinoid system itself, but rather to other neural mechanisms.
Why it matters
Understanding why some individuals are more sensitive to cannabis is crucial for identifying who is at risk for cannabis-related psychosis. This study narrows the search by ruling out developmental differences in the endocannabinoid system as the explanation, redirecting attention toward other neural pathways that may mediate this vulnerability.
The numbers in context
8 developmental time points assessed: postnatal days 7, 10, 14, 21, 28, 35, 49, and 161. 4 endocannabinoid markers measured: CB1R, DAGLalpha, MGLL, ABHD6. No sex differences found in any marker. No Nrg1 genotype differences at any time point. Endocannabinoid markers peaked around PND 21-35.
How the study worked
Male and female heterozygous Nrg1 transmembrane domain mutant mice and wild-type littermates were assessed at postnatal days 7, 10, 14, 21, 28, 35, 49, and 161. Quantitative PCR measured mRNA expression of CB1R, DAGLalpha, MGLL, and ABHD6 in the prelimbic cortex and hippocampus.
What this study cannot tell us
Only mRNA expression was measured, not protein levels or functional receptor activity. The four markers studied represent only part of the endocannabinoid system. Other endocannabinoid components not measured may show genotype differences. The Nrg1 mutation is one of many schizophrenia risk genes, and findings may not generalize to other genetic risk factors.
How to read the evidence
This is a controlled animal study with comprehensive developmental time course, providing preliminary evidence ruling out one potential mechanism of cannabis vulnerability.
When this study was published
Published in 2018. Research on genetic determinants of cannabis sensitivity continues.
The bigger picture
The developmental period around postnatal day 21-35 in mice (roughly equivalent to adolescence) showed the peak expression of endocannabinoid system components. This developmental window may correspond to the period of greatest vulnerability to cannabis exposure in humans, though the genetic risk factor studied here does not appear to act through this system.
Questions still open
- If not the endocannabinoid system, what neural mechanisms explain the heightened cannabis sensitivity in Nrg1 mutant mice? Would measuring endocannabinoid levels (rather than enzyme expression) reveal genotype differences? Do other schizophrenia risk genes affect the endocannabinoid system developmental trajectory?
Common questions
Does the schizophrenia risk gene change the endocannabinoid system?
When does the endocannabinoid system develop?
Read the original research
The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice.
Frontiers in psychiatry, 9, 11
Citation
Chesworth, Rose; Long, Leonora E; Weickert, Cynthia Shannon; Karl, Tim. (2018). The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice.. Frontiers in psychiatry, 9, 11. https://doi.org/10.3389/fpsyt.2018.00011
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