Prenatal cannabinoid exposure alters excitation-inhibition balance through glutamate and GABA receptor-mediated signaling.
Priyanka D Pinky, Warren D Smith, Miles T Wiley, Jenna Bloemer, Vasiliki Syropoulou, Iva Durdanovic, Sharay E Setti, Jeremiah C Pfitzer, Savannah R Perman, Kawsar U Chowdhury, Kelli L McDonald, Michael W Gramlich, Subhrajit Bhattacharya, Vishnu Suppiramaniam, Miranda N Reed
Journal of Biological Chemistry July 2026 DOI: 10.1016/j.jbc.2026.113196 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical rodent study Peer reviewed |
|---|---|
| Population | Adolescent offspring of rodents prenatally exposed to THC |
| Intervention | delta-9-tetrahydrocannabinol (THC) |
| Topics | Cannabis Neuroplasticity |
| Keywords | Adolescence Behavior Cannabinoid Developmental Glutamate Memory Prenatal |
| Key points | Prenatal THC exposure in a rodent model caused persistent hippocampal-dependent memory deficits and impaired synaptic plasticity in adolescent offspring, with reduced AMPAR-mediated transmission and an excitation/inhibition imbalance. Postsynaptic glutamatergic proteins (GluA1, GluN2A, GluN2B, PSD95) were selectively downregulated while presynaptic markers were unchanged, and inhibitory networks showed region-specific reorganization. The authors argue that disrupted GABAergic signaling may be a therapeutic target for cognitive deficits from prenatal cannabis exposure. |
Abstract
The growing perception that marijuana is safe during pregnancy has led to a marked increase in prenatal cannabis use, raising concerns about its long-term effects on brain development and cognition. This study investigated the consequences of prenatal delta-9-tetrahydrocannabinol (THC) exposure on hippocampal circuit function, synaptic plasticity, and memory in adolescent offspring using a rodent model. We found that prenatal THC exposure resulted in persistent deficits in hippocampal-dependent memory and significant disruptions in synaptic plasticity, including impaired long-term potentiation and increased long-term depression. Electrophysiological analyses revealed reduced AMPAR-mediated synaptic transmission and a shift toward increased inhibitory signaling, suggesting an excitation/inhibition (E/I) imbalance in the hippocampus. These functional changes were accompanied by selective downregulation of postsynaptic glutamatergic proteins (GluA1, GluN2A, GluN2B, and PSD95), while presynaptic glutamate markers remained unchanged. Notably, immunohistochemical and anatomical analyses demonstrated region-specific reorganization of inhibitory networks, including altered distribution and colocalization of cannabinoid 1 receptor (CB1R) and vesicular GABA transporter (VGAT) across hippocampal subregions. Together, our results reveal that prenatal THC exposure leads to coordinated functional and structural remodeling of hippocampal circuits, producing a lasting E/I imbalance and memory impairments during adolescence. These findings highlight disrupted GABAergic signaling as a potential therapeutic target for mitigating cognitive deficits resulting from prenatal cannabis exposure.
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Citations in the library
Cites 7
- Prenatal THC exposure drives sex-specific alterations in spatial memory and hippocampal excitatory/inhibitory balance in adolescent rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie December 1, 2024
- Effects of Cannabis on Glutamatergic Neurotransmission: The Interplay between Cannabinoids and Glutamate. Cells June 29, 2024
- Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring: Focus on Specific Markers of Neuroplasticity. Pharmaceutics February 17, 2023
- Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone Nature Neuroscience September 11, 2019
- Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proceedings of the National Academy of Sciences March 27, 2018
and 2 more in the library