Figure 1. THC deregulating effect on microtubule dynamics in growth cones.

An integrated signaling transduced by CB₁ via JNKs and executed by SCG10 is disrupted by THC during the corticogenesis of prenatal brains exposed to a dose of THC (3 mg/kg/day, embryonic day E5.5–17.5) non-aversive to dams. SCG10 is normally enriched near CB₁ receptors in growth cone-like structures, mainly traversing the pallio-subpallial boundary, where its microtubule-destabilizing action represents an important factor for the dynamic assembly and disassembly of growth cone microtubules during axonal elongation. Phosphorylation at Ser62 and Ser73 by JNK1, the active brain-specific JNK isoform, exerted also through the tonic action of the endocannabinoid 2-AG, promotes SCG10 degradation with ensuing fine regulation of microtubule dynamics and axodendritic morphology. Chronic THC administration during cortical development disrupts this action through both reduced 2-AG biosynthesis and CB₁ expression, and excessive SCG10 phosphorylation and degradation. THC also increases the formation of F-actin-rich filopodia in the distant motile axon segment. 2-AG, 2-arachidonoylglycerol; CB₁R, cannabinoid receptor type 1; JNK1, c-Jun N-terminal kinase 1; MAPs, microtubule-associated proteins; THC, Δ⁹-tetrahydrocannabinol; SCG10, superior cervical ganglion 10.