BDNF-Deficient Male Mice Became Hypersensitive to Cannabinoid Effects on Sensory Gating After Chronic Exposure | Research

The takeaway

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.

Read this if you are interested in how genetic vulnerability and cannabis use might interact to affect brain function.

Sex-specific effect: only male two-hit mice showed hypersensitivity to cannabinoid challenge

What the researchers 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.

Why it 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 numbers in context

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 the study worked

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.

What this study cannot 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.

How to read the evidence

Animal "two-hit" model with mixed results; preliminary evidence for gene-environment interaction.

When this study was published

Published in 2013. Gene-environment interaction models of psychosis continue to evolve.

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.

Questions still open

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?

Common 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.

Read the original research

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

View on PubMed ↗Publisher’s paper ↗

Citation

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