Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure
Adán de Salas-Quiroga, Daniel García-Rincón, Daniel Gómez-Domínguez, Manuel Valero, Samuel Simón-Sánchez, Juan Paraíso‐Luna, José Aguareles, Mitona Pujadas, Carolina Muguruza, Luis Felipe Callado, Beat Lutz, Manuel Guzmán, Liset Menéndez de la Prida, Ismael Galve-Roperh
Neuropsychopharmacology January 26, 2020 DOI: 10.1038/s41386-020-0621-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Mice prenatally exposed to THC, including conditional CB1R knockout mice |
| Intervention | Δ9-tetrahydrocannabinol (THC) |
| Topics | Cannabis |
| Citations | 84 |
| Key findings | Prenatal THC exposure in mice caused spatial memory impairment, brain hyperexcitability, altered hippocampal oscillations, and a reduction of CCK-containing interneurons, with effects seen only in male offspring. The interneuron loss was absent when CB1 receptors were selectively removed from GABAergic interneurons, indicating a cell-autonomous THC action. The authors propose this interneuronopathy explains the sex-dimorphic cognitive deficits. |
Abstract
Abstract Prenatal exposure to Δ9-tetrahydrocannabinol (THC), the most prominent active constituent of cannabis, alters neurodevelopmental plasticity with a long-term functional impact on adult offspring. Specifically, THC affects the development of pyramidal neurons and GABAergic interneurons via cannabinoid CB1 receptors (CB1R). However, the particular contribution of these two neuronal lineages to the behavioral alterations and functional deficits induced by THC is still unclear. Here, by using conditional CB1R knockout mice, we investigated the neurodevelopmental consequences of prenatal THC exposure in adulthood, as well as their potential sex differences. Adult mice that had been exposed to THC during embryonic development showed altered hippocampal oscillations, brain hyperexcitability, and spatial memory impairment. Remarkably, we found a clear sexual dimorphism in these effects, with males being selectively affected. At the neuronal level, we found a striking interneuronopathy of CCK-containing interneurons in the hippocampus, which was restricted to male progeny. This THC-induced CCK-interneuron reduction was not evident in mice lacking CB1R selectively in GABAergic interneurons, thus pointing to a cell-autonomous THC action. In vivo electrophysiological recordings of hippocampal LFPs revealed alterations in hippocampal oscillations confined to the stratum pyramidale of CA1 in male offspring. In addition, sharp-wave ripples, a major high-frequency oscillation crucial for learning and memory consolidation, were also altered, pointing to aberrant circuitries caused by persistent reduction of CCK+ basket cells. Taken together, these findings provide a mechanistic explanation for the long-term interneuronopathy responsible for the sex-dimorphic cognitive impairment induced by prenatal THC.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors Mice | 2015 | Preclinical study | |
| Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). hMDR1- and hBCRP-transfected HEK293 cells and hMDR1- and hBCRP-MDCKII cells | 2010 | In vitro study | |
| Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway Mice exposed to chronic THC early in life | 2018 | Animal experimental study | |
| Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain Spontaneously hypertensive rats (SHRs) and Wistar rats | 2014 | Animal experimental study | |
| Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors Rats | 2018 | Experimental study |
Citations in the library
Cited by 11
- Vaporized Δ9-tetrahydrocannabinol exposure in utero has negative effects on attention in a dose- and sex-dependent manner. Pharmacology, Biochemistry, and Behavior September 1, 2024
- Adult Rat Offspring Exposed to THC during Gestation Exhibit Distinct Biomolecular Changes Identified by X-ray Fluorescence Imaging and Fourier Transform Infrared Spectroscopy in Cortico-Limbic Circuits. ACS Chemical Neuroscience February 18, 2026
- Regulation of neural connectivity and oscillations by cannabinoids: A review. Neuroscience & Biobehavioral Reviews September 7, 2026
- Perinatal LC-ω-3-PUFA supplementation offsets prenatal THC-induced cognitive deficit via sex-specific modulation of hippocampal neuroplasticity. European Journal of Pharmacology June 1, 2026
- Gestational THC exposure perturbates hippocampal mitochondrial respiration in the memory-impaired adolescent progeny: Is there a role for mitochondrial CB1 receptor? Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie June 2025
and 6 more in the library
Cites 8
- Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone Nature Neuroscience September 11, 2019
- Adolescent Cannabinoid Exposure Induces a Persistent Sub-Cortical Hyper-Dopaminergic State and Associated Molecular Adaptations in the Prefrontal Cortex. Cerebral Cortex February 1, 2017
- Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Molecular Psychiatry January 2017
- The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia. Biological Psychiatry April 1, 2016
- Sex Differences in Cannabis Use and Effects: A Cross-Sectional Survey of Cannabis Users. Cannabis and Cannabinoid Research 2016
and 3 more in the library