The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…Overall, the early expression and functionality of the CB 1 receptor during nervous system development and its transient and atypical localization in prenatal stages suggest a specific role of the ECB system in human brain development, with potential implications in neuropsychiatric disorders [6,26]. [31,32], its expression pattern in the nervous system of the zebrafish is suggestive of its involvement in neurogenesis [33]. Neurospheres (non-adherent in vitro culture of NP cells) from embryonic and postnatal development stages express CB 1 receptors and the anandamide (AEA)-degrading enzyme fatty acid amide hydrolase (FAAH), and elevations in their intracellular Ca 2þ concentration increase ECB production [29].…”

Wiring and firing neuronal networks: endocannabinoids take center stage

“…Likely eCB actions on neural stem and progenitor cells are underscored by ample DAGL expression in neurogenic telencephalic niches [32,33], CB 1 R/CB 2 R and metabolic enzyme expression in neurospheres, and by the sensitivity of neural stem cells to pharmacological and genetic disruption of eCB signaling [32][33][34][35] (Figure 2). A robust increase in CB 1 R expression in immature post-mitotic neurons becomes evident as soon as neuronal lineagecommitment occurs [36][37][38]. The presence of an eCB-rich transient territory marked by DAGL-expressing cells at the outermost border of the subventricular zone (SVZ) facing the first layer of CB 1 R-positive post-mitotic neurons (corresponding to cells entering the intermediate zone in the cerebrum) [33] suggests that a propulsive eCB tone exists in the developing neocortex that facilitates radial migration of immature pyramidal cells and GABAergic interneurons [25] from the SVZ and deep migratory stream, respectively ( Figure 2).…”

“…Prominent DAGLα/β localization to pyramidal cell axons is required for axonal elongation through cell-autonomous signaling [33,37] (Figure 3). De novo synthesized 2-AG can exert either autocrine regulation via CB 1 Rs distributed along the longitudinal axis of the growing axon, or paracrine signaling amongst neighboring axons, thus maintaining the integrity of an eCB-rich axonal trajectory.…”

“…Through 2-AG release, pre-existing excitatory axons will thus determine the spatial distribution of inhibitory afferents along the dendritic arbors of pyramidal neurons. This novel mechanism of eCB-driven synapse segregation is further supported by the fact that CB 1 R and DAGL levels peak in cortical neurons throughout the period of axonal elongation with progressively reduced CB 1 R expression and increased somatodendritic DAGL targeting as synaptogenesis terminates [12,14,33,36,37]. Another striking feature of our proposed model of neuronal network formation is that the ratio of CB 1 R and DAGL levels between glutamatergic and GABAergic neurons remains steady throughout neuronal specification and postnatal function.…”

“…Physiological situations favoring antagonistic THC actions include low receptor density (e.g., pyramidal cells) or limiting downstream signaling molecules (e.g., during early specification events). Intriguingly, high-affinity antagonists at CB 1 Rs including, among other compounds, AM251, rimonabant, and taranabant, appear to exert even more powerful effects on developing glutamatergic neurons [33,37] by inhibiting axon fasciculation and postsynaptic target selection. A cell-autonomous eCB tone provided by DAGL activity in developing axons may define the cellular basis for undesired effects of CB 1 R antagonists, and account for the cortical delamination and perturbed long-range axon patterning induced by AM251 and rimonabant [33,37].…”