Prenatal THC Caused Long-Term Cognitive Problems in Rat Offspring Through Sex-Specific Mechanisms in the Prefrontal Cortex and Hippocampus
Prenatal THC exposure produced lasting cognitive deficits in both male and female rat offspring, but through highly divergent sex-specific mechanisms involving different patterns of neural hyperactivity, protein expression changes, and fatty acid deficiencies in the prefrontal cortex and hippocampus.
Quick Facts
What This Study Found
Both sexes showed long-term cognitive deficits and hyperactive prefrontal pyramidal neurons. Males showed hippocampal hypoactivity while females showed hyperactivity. Cortical oscillatory activity was strongly sex-divergent. Protein expression disturbances (D1R/D2R, NMDA-2B, synaptophysin, gephyrin, GAD67, PPARalpha) appeared primarily at PD120 in both regions for males, but only in vHIPP for females. MALDI imaging revealed region-, age-, and sex-specific deficiencies in DHA and arachidonic acid.
Key Numbers
Both sexes: PFC pyramidal neuron hyperactivity, cognitive deficits. Males: vHIPP hypoactivity, disturbances in both PFC and vHIPP. Females: vHIPP hyperactivity, disturbances mainly in vHIPP. PUFA deficiencies (DHA, ARA) region- and sex-specific.
How They Did This
Rodent model of prenatal cannabis exposure with comprehensive analysis: electrophysiology, cortical oscillations, protein expression at PD21 and PD120, and MALDI imaging mass spectrometry for lipid analysis in prefrontal cortex and hippocampus.
Why This Research Matters
This is one of the most comprehensive studies of prenatal THC effects, showing that while both sexes suffer cognitively, the underlying biology is radically different. This means treatments for prenatal cannabis effects may need to be sex-specific.
The Bigger Picture
The discovery that prenatal THC depletes specific fatty acids (DHA and arachidonic acid) in brain regions is particularly novel. These PUFAs are essential for endocannabinoid system function, suggesting THC disrupts the very signaling system it activates, creating a long-term deficit.
What This Study Doesn't Tell Us
Rat model with injected THC (not smoked cannabis). Sex-specific findings are at the biological level and may not directly predict sex-specific behavioral outcomes in humans. MALDI imaging provides spatial distribution but not functional significance. Single THC dose regimen.
Questions This Raises
- ?Could DHA supplementation during pregnancy protect against THC-induced brain changes?
- ?Do sex-specific mechanisms explain why some epidemiological studies find different outcomes in boys vs. girls after prenatal cannabis exposure?
Trust & Context
- Key Stat:
- Male and female offspring had the same cognitive deficits but completely different brain mechanisms
- Evidence Grade:
- Comprehensive preclinical study with multiple complementary methods. Published in Molecular Psychiatry. Strong mechanistic evidence.
- Study Age:
- Published in 2023 in Molecular Psychiatry.
- Original Title:
- Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.
- Published In:
- Molecular psychiatry, 28(10), 4234-4250 (2023)
- Authors:
- Sarikahya, Mohammed H(8), Cousineau, Samantha L(3), De Felice, Marta(6), Szkudlarek, Hanna J, Wong, Karen K W, DeVuono, Marieka V, Lee, Kendrick, Rodríguez-Ruiz, Mar, Gummerson, Dana, Proud, Emma, Ng, Tsun Hay Jason, Hudson, Roger, Jung, Tony, Hardy, Daniel B, Yeung, Ken K-C, Schmid, Susanne, Rushlow, Walter, Laviolette, Steven R
- Database ID:
- RTHC-04914
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Does prenatal THC affect boys and girls differently?
Both sexes showed lasting cognitive deficits, but the underlying brain mechanisms were radically different. Males had hippocampal underactivity while females had overactivity, with different patterns of protein and fatty acid changes.
What brain changes does prenatal THC cause?
This study found overactive prefrontal neurons, disrupted brain oscillations, altered receptor proteins, and depleted essential fatty acids (DHA, arachidonic acid) in the prefrontal cortex and hippocampus.
Read More on RethinkTHC
Cite This Study
https://rethinkthc.com/research/RTHC-04914APA
Sarikahya, Mohammed H; Cousineau, Samantha L; De Felice, Marta; Szkudlarek, Hanna J; Wong, Karen K W; DeVuono, Marieka V; Lee, Kendrick; Rodríguez-Ruiz, Mar; Gummerson, Dana; Proud, Emma; Ng, Tsun Hay Jason; Hudson, Roger; Jung, Tony; Hardy, Daniel B; Yeung, Ken K-C; Schmid, Susanne; Rushlow, Walter; Laviolette, Steven R. (2023). Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.. Molecular psychiatry, 28(10), 4234-4250. https://doi.org/10.1038/s41380-023-02190-0
MLA
Sarikahya, Mohammed H, et al. "Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.." Molecular psychiatry, 2023. https://doi.org/10.1038/s41380-023-02190-0
RethinkTHC
RethinkTHC Research Database. "Prenatal THC exposure induces long-term, sex-dependent cogni..." RTHC-04914. Retrieved from https://rethinkthc.com/research/sarikahya-2023-prenatal-thc-exposure-induces
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.