Cannabinoid Receptor CB2 Modulates Axon Guidance

Navigation of retinal projections towards their targets is regulated by guidance molecules and growth cone transduction mechanisms. Here, we present in vitro and in vivo evidences that the cannabinoid receptor 2 (CB2R) is expressed along the retino-thalamic pathway and exerts a modulatory action on axon guidance. These effects are specific to CB2R since no changes were observed in mice where the gene coding for this receptor was altered (cnr2(-/-)). The CB2R induced morphological changes observed at the growth cone are PKA dependent and require the presence of the netrin-1 receptor, Deleted in Colorectal Cancer. Interfering with endogenous CB2R signalling using pharmacological agents increased retinal axon length and induced aberrant projections. Additionally, cnr2(-/-) mice showed abnormal eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus (dLGN) indicating CB2R's implication in retinothalamic development. Overall, this study demonstrates that the contribution of endocannabinoids to brain development is not solely mediated by CB1R, but also involves CB2R.