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Miswiring the brain: Δ 9 ‐tetrahydrocannabinol disrupts cortical development by inducing an SCG 10/stathmin‐2 degradation pathway
Author(s) -
Tortoriello Giuseppe,
Morris Claudia V,
Alpar Alan,
Fuzik Janos,
Shirran Sally L,
Calvigioni Daniela,
Keimpema Erik,
Botting Catherine H,
Reinecke Kirstin,
Herdegen Thomas,
Courtney Michael,
Hurd Yasmin L,
Harkany Tibor
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/embj.201386035
Subject(s) - stathmin , biology , tetrahydrocannabinol , neuroscience , microbiology and biotechnology , receptor , biochemistry , phosphorylation , cannabinoid
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 CB 1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC‐sensitive neuronal proteome we identify Superior Cervical Ganglion 10 ( SCG 10)/stathmin‐2, a microtubule‐binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG 10 mRNA and protein reduced in the hippocampus of midgestational human cannabis‐exposed fetuses, defining SCG 10 as the first cannabis‐driven molecular effector in the developing cerebrum. CB 1 cannabinoid receptor activation recruits c‐Jun N‐terminal kinases to phosphorylate SCG 10, 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.