Concerted Action of CB1 Cannabinoid Receptor and Deleted in Colorectal Cancer in Axon Guidance

TLDR

Endocannabinoids act as retrograde neurotransmitters and, together with CB1 receptors and metabolizing enzymes, are implicated in embryonic neuronal proliferation, differentiation, migration, axon guidance, and synaptogenesis. This study investigates the functional role of CB1 receptors in the developing visual system, focusing on their influence on axon growth and retinothalamic development. Pharmacological activation of CB1R collapses growth cones and reduces retinal projection growth, while inhibition promotes growth and aberrant projections; CB1R modulates DCC trafficking via PKA, and loss of DCC abolishes CB1R‑induced growth‑cone reorganization, revealing a CB1R–DCC mechanism guiding axons.

Abstract

Endocannabinoids (eCBs) are retrograde neurotransmitters that modulate the function of many types of synapses. The presence of eCBs, their CB1 receptor (CB1R), and metabolizing enzymes at embryonic and early postnatal periods have been linked to developmental processes such as neuronal proliferation, differentiation, and migration, axon guidance, and synaptogenesis. Here, we demonstrate the presence of a functional eCB system in the developing visual system and the role of CB1R during axon growth and retinothalamic development. Pharmacological treatment of retinal explants and primary cortical neuron cultures with ACEA, a selective CB1R agonist, induced a collapse of the growth cone (GC). Furthermore the application of AM251, a CB1R inverse agonist, to the neuronal cultures increased the surface area of GC. In vivo , intraocular injection of ACEA diminished retinal projection growth, while AM251 promoted growth and caused aberrant projections. In addition, compared with their wild-type littermates, CB1R-deficient adult mice revealed a lower level of eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus. Finally, we found that pharmacological modulation of CB1R affected the trafficking of Deleted in colorectal cancer (DCC) receptor to the plasma membrane in a PKA-dependent manner. Moreover, pharmacological inhibition or genetic inactivation of DCC abolished the CB1R-induced reorganization of the GC. Overall, these findings establish a mechanism by which the CB1R influences GC behavior and nervous system development in concerted action with DCC.