Kinesin-1-mediated axonal transport of CB1 receptors is required for cannabinoid-dependent axonal growth and guidance.

Endocannabinoids modulate growth cone dynamics and axonal pathfinding through the stimulation of cannabinoid type-1 receptors (CB1R) which function depends on its delivery and precise presentation at the growth cone surface. However, the mechanism involved in the axonal transport of CB1R and its role in eCB signaling remains elusive. Kinesin-1 mutations have been identified in patients with abnormal cortical development and impaired white matter integrity. We found defects in axonal pathfinding and fasciculation in mice lacking the kinesin light chain 1 (KLC1^-/-) subunit of the kinesin-1 molecular motor. Reduced levels of CB1R were observed in corticofugal projections and growth cones in KLC1^-/- By live-cell imaging of CB1R-eGFP we characterized the axonal transport of CB1R vesicles in control conditions and the defects in transport that arise in KLC1 deleted neurons. Cofilin activation, which is necessary for actin dynamics during growth cone remodeling, is impaired in KLC1^-/- cortex. KLC1^-/- neurons showed expanded growth cones that resulted unresponsive to CB1R-induced axonal elongation. Together, our data reveal the relevance of kinesin-1 in CB1R axonal transport and in endocannabinoid signaling during brain wiring.