BDNF-Deficient Male Mice Became Hypersensitive to Cannabinoid Effects on Sensory Gating After Chronic Exposure
Male mice with reduced BDNF who received chronic cannabinoid treatment during young adulthood became hypersensitive to acute cannabinoid effects on sensory gating, with increased CB1 receptor density in the nucleus accumbens.
Quick Facts
What This Study Found
Researchers tested a "two-hit" model for schizophrenia vulnerability: BDNF deficiency (genetic hit) combined with chronic young-adult cannabinoid exposure (environmental hit). BDNF heterozygous mice had lower baseline prepulse inhibition (PPI, a measure of sensory gating relevant to schizophrenia) and increased startle responses.
Chronic cannabinoid treatment during weeks 6-8 of life did not affect memory (Y-maze or novel object recognition) in any group. However, male BDNF-deficient mice that received chronic cannabinoid treatment showed marked PPI increases when given acute cannabinoid, while no other group showed this effect. This correlated with increased CB1 receptor density specifically in the nucleus accumbens.
Key Numbers
BDNF HET: lower baseline PPI, higher startle. Male two-hit mice (BDNF HET + chronic CP): marked PPI increase with acute CP. CB1 receptor binding increased in nucleus accumbens of male two-hit mice only. No memory effects in any group.
How They Did This
BDNF heterozygous and wild-type mice treated with CP55,940 during weeks 6-8 of life. After 2-week delay: Y-maze, novel object recognition, PPI with acute CP55,940 challenge. CB1 receptor binding autoradiography in nucleus accumbens and caudate.
Why This Research Matters
This study models how genetic vulnerability (reduced neurotrophic support) and environmental exposure (adolescent cannabis use) might interact to alter brain function in ways relevant to schizophrenia. The sex-specific effect (males only) aligns with the higher incidence of schizophrenia in males.
The Bigger Picture
The "two-hit" hypothesis of schizophrenia proposes that genetic vulnerability combined with environmental stressors produces the disorder. This study provides partial support by showing sex-specific sensitization of sensory gating circuits, though the PPI increase (rather than decrease) was unexpected and requires interpretation.
What This Study Doesn't Tell Us
The PPI increase with acute cannabinoid is difficult to interpret, as PPI deficits (not increases) are the typical schizophrenia-relevant measure. The CP55,940 dose and regimen may not model human cannabis use. BDNF heterozygous mice are an imperfect model of schizophrenia vulnerability. Only one brain region showed receptor changes.
Questions This Raises
- ?Why did the two-hit combination increase rather than decrease PPI?
- ?Does the nucleus accumbens CB1 upregulation have functional consequences beyond PPI?
- ?Would different cannabinoids or exposure windows produce different interactions with BDNF deficiency?
Trust & Context
- Key Stat:
- Sex-specific effect: only male two-hit mice showed hypersensitivity to cannabinoid challenge
- Evidence Grade:
- Animal "two-hit" model with mixed results; preliminary evidence for gene-environment interaction.
- Study Age:
- Published in 2013. Gene-environment interaction models of psychosis continue to evolve.
- Original Title:
- An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice.
- Published In:
- Frontiers in behavioral neuroscience, 7, 149 (2013)
- Authors:
- Klug, Maren, van den Buuse, Maarten
- Database ID:
- RTHC-00692
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Does this mean cannabis is more dangerous for people with certain genes?
This mouse study suggests that genetic factors (specifically reduced BDNF) can change how the brain responds to chronic cannabinoid exposure. The interaction was sex-specific, affecting only males. While this cannot be directly applied to humans, it supports the broader concept that genetic background influences cannabis vulnerability, which aligns with human epidemiological findings.
What is BDNF and why does it matter?
BDNF (brain-derived neurotrophic factor) is a protein that supports the survival and growth of brain cells. Reduced BDNF has been found in schizophrenia patients. Mice with reduced BDNF already showed some brain function differences (lower sensory gating), and adding chronic cannabinoid exposure during young adulthood created additional changes specifically in male mice.
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Cite This Study
https://rethinkthc.com/research/RTHC-00692APA
Klug, Maren; van den Buuse, Maarten. (2013). An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice.. Frontiers in behavioral neuroscience, 7, 149. https://doi.org/10.3389/fnbeh.2013.00149
MLA
Klug, Maren, et al. "An investigation into "two hit" effects of BDNF deficiency and young-adult cannabinoid receptor stimulation on prepulse inhibition regulation and memory in mice.." Frontiers in behavioral neuroscience, 2013. https://doi.org/10.3389/fnbeh.2013.00149
RethinkTHC
RethinkTHC Research Database. "An investigation into "two hit" effects of BDNF deficiency a..." RTHC-00692. Retrieved from https://rethinkthc.com/research/klug-2013-an-investigation-into-two
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.