A schizophrenia risk gene did not alter the developmental trajectory of the brain's endocannabinoid system in mice
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Endocannabinoid markers peaked at PND 21-35 but showed no difference in at-risk mice
- Evidence Grade:
- This is a controlled animal study with comprehensive developmental time course, providing preliminary evidence ruling out one potential mechanism of cannabis vulnerability.
- Study Age:
- Published in 2018. Research on genetic determinants of cannabis sensitivity continues.
- Original Title:
- The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice.
- Published In:
- Frontiers in psychiatry, 9, 11 (2018)
- Authors:
- Chesworth, Rose(3), Long, Leonora E, Weickert, Cynthia Shannon, Karl, Tim
- Database ID:
- RTHC-01620
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Does the schizophrenia risk gene change the endocannabinoid system?
In this study, no. Despite being known to increase cannabis sensitivity, the Nrg1 mutation did not alter the developmental trajectory of four key endocannabinoid system components. Other neural mechanisms must explain the heightened vulnerability.
When does the endocannabinoid system develop?
In mice, key endocannabinoid markers peaked around postnatal days 21-35 (roughly equivalent to adolescence) before declining and stabilizing. This developmental peak may correspond to the period of greatest cannabis vulnerability in humans.
Read More on RethinkTHC
- THC-amygdala-anxiety-brain
- anandamide-weed-withdrawal
- cannabinoid-receptors-recovery-time
- cannabis-developing-brain-teenagers
- cant-enjoy-anything-without-weed
- dopamine-recovery-after-quitting-weed
- endocannabinoid-system-explained-simply
- endocannabinoid-system-withdrawal
- nervous-system-weed-withdrawal-fight-flight
- teen-weed-use-under-18-effects-brain
- thc-brain-withdrawal
- thc-prefrontal-cortex-brain-effects
- weed-cortisol-stress-hormones
- weed-memory-loss-recovery
- weed-motivation-amotivational-syndrome
- weed-nervous-system-effects
- weed-reward-system-brain
Cite This Study
https://rethinkthc.com/research/RTHC-01620APA
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
MLA
Chesworth, Rose, et al. "The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice.." Frontiers in psychiatry, 2018. https://doi.org/10.3389/fpsyt.2018.00011
RethinkTHC
RethinkTHC Research Database. "The Endocannabinoid System across Postnatal Development in T..." RTHC-01620. Retrieved from https://rethinkthc.com/research/chesworth-2018-the-endocannabinoid-system-across
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.