Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway.
Giuseppe Tortoriello, Claudia V Morris, Alán Alpár, Janos Fuzik, Sally L Shirran, Daniela Calvigioni, Erik Keimpema, Catherine H Botting, Kirstin Reinecke, Thomas Herdegen, Michael Courtney, Yasmin L. Hurd, Tibor Harkany
The EMBO journal April 1, 2014 DOI: 10.1002/embj.201386035 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science study (preclinical and human fetal tissue analysis) Peer reviewed |
|---|---|
| Population | Mice and midgestational human fetuses exposed to cannabis in utero |
| Intervention | THC |
| Topics | Cannabis |
| Key points | Repeated THC exposure disrupts endocannabinoid signaling and CB1 receptor dynamics, leading to JNK-mediated phosphorylation and degradation of SCG10/stathmin-2 in axons, which alters microtubule stability and axon morphology. SCG10 mRNA and protein are reduced in the hippocampus of midgestational human cannabis-exposed fetuses, identifying SCG10 as a molecular effector of cannabis in the developing cerebrum. |
Abstract
Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ(9)-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 14
- Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders Frontiers in Pharmacology May 23, 2017
- Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure Neuropsychopharmacology January 26, 2020
- A Proteomic View of Cellular and Molecular Effects of Cannabis Biomolecules September 27, 2021
- 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
- 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
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