Cannabinoid-induced axonal elongation and growth cone remodeling depend on KLC1-mediated axonal transport of CB1 receptors.

M ALLOATTI; TL FALZONE; TMM SAEZ; A HALLBERG; I FERNÁNDEZ BESSONE

Puerto Varas

Workshop; IUBMB FOCUSED MEETING ON EMERGING CONCEPTS OF THE NEURONAL CYTOSKELETON; 2017

EMBO

Endocannabinoid (eCB) signaling modulates axonal pathfinding and fasciculation of long-range connections by regulating the axonal growth cone-turning decision through the activation of the cannabinoid type 1 receptor (CB1R). The activation of CB1R in the growth cone surface impacted on actin polymerization and stability by coupling to small Rho-GTPases, leading to their collapse. The trafficking and subcellular localization of CB1R is highly dynamic and spatiotemporal regulated in developing neurons. However, the mechanisms involved in CB1R axonal transport and its role in eCB signaling remain elusive. We report that mice lacking the kinesin light chain 1 (KLC1), a subunit of the anterograde motor kinesin-1, develop significant defects in axonal pathfinding at a critical choice point such as the corticostriatal boundary. Moreover, hyperfasciculation of corticofugal and thalamocortical axons and a reduced CB1R protein level in corticofugal axons were observed in KLC1-/- neonatal mice. Live cell imaging of CB1R-eGFP vesicles in KLC1-/- neurons revealed the dependency of KLC1 in CB1R axonal transport to thegrowth cone. Cofilin activation, which is necessary for actin dynamics, was impaired in KLC1-/- developing cerebral cortex. Finally, KLC1-/- primary cortical neurons does not respond to CB1R-induced axonal elongation and growth cone remodeling. Our data uncover that eCB signaling during brain wiring depends on kinesin-1-mediated axonal transport of CB1R to growth cones. Knowledge on the regulation of CB1R axonal transport during the establishment of neuronal connections can contribute towards understanding the mechanistic underlying human neurodevelopmental disorders associated with brain wiring defects.