Type-1 Cannabinoid Receptor Signaling in Neuronal Development

The type-1 cannabinoid receptor (CB1R) was initially identified as the neuronal target of Δ(9)-tetrahydrocannabinol (THC), the major psychoactive substance of marijuana. This receptor is one of the most abundant G-protein-coupled receptors in the adult brain, the target of endocannabinoid ligands and a well-characterized retrograde synaptic regulator. However, CB1Rs are also highly and often transiently expressed in neuronal populations in the embryonic and early postnatal brain, even before the formation of synapses. This suggests important physiological roles for CB1Rs during neuronal development. Several recent reviews have summarized our knowledge about the role of the endocannabinoid (eCB) system in neurodevelopment and neurotransmission by focusing on the metabolism of endocannabinoid molecules. Here, we review current knowledge about the effects of the modulation of CB1R signaling during the different phases of brain development. More precisely, we focus on reports that directly implicate CB1Rs during progenitor cell migration and differentiation, neurite outgrowth, axonal pathfinding and synaptogenesis. Based on theoretical considerations and on the reviewed experimental data, we propose a new model to explain the diversity of experimental findings on eCB signaling on neurite growth and axonal pathfinding. In our model, cell-autonomus and paracrine eCBs acting on CB1Rs are part of a global inhibitory network of cytoskeletal effectors, which act in concert with positive-feedback local-excitation loops, to ultimately yield highly polarized neurons.