Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway

Abstract Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Delta(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. Synopsis image Delta(9)-tetrahydrocannabinol (THC), the major psychoactive component from cannabis, is shown to activate a molecular cascade modulating SCG10/stathmin-2 availability and function, thus inducing cytoskeletal modifications in fetal neurons. In vivo experiments demonstrate that THC disrupts endocannabinoid signaling and acts as a functional antagonist in the fetal brain. C-Jun terminal kinase links CB1 cannabinoid receptor and SCG10/stathmin-2 phosphorylation and degradation. Maternal cannabis smoking reduces SCG10/stathmin-2 mRNA and protein expression in human fetal brains, identifying SCG10/stathmin-2 as a key molecular effector mediating adverse cannabis effects.