Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration

Abstract

Cannabinoid type 1 receptor (CB1R) is expressed and participates in several aspects of cerebral cortex embryonic development as demonstrated with whole-transcriptome mRNA sequencing and other contemporary methods. However, the cellular location of CB1R, which helps to specify molecular mechanisms, remains to be documented. Using three-dimensional (3D) electron microscopic reconstruction, we examined CB1R immunolabeling in proliferating neural stem cells (NSCs) and migrating neurons in the embryonic mouse (Mus musculus) and rhesus macaque (Macaca mulatta) cerebral cortex. We found that the mitotic and postmitotic ventricular and subventricular zone (VZ and SVZ) cells are immunonegative in both species while radially migrating neurons in the intermediate zone (IZ) and cortical plate (CP) contain CB1R-positive intracellular vesicles. CB1R immunolabeling was more numerous and more extensive in monkeys compared to mice. In CB1R-knock out mice, projection neurons in the IZ show migration abnormalities such as an increased number of lateral processes. Thus, in radially migrating neurons CB1R provides a molecular substrate for the regulation of cell movement. Undetectable level of CB1R in VZ/SVZ cells indicates that previously suggested direct CB1R-transmitted regulation of cellular proliferation and fate determination demands rigorous re-examination. More abundant CB1R expression in monkey compared to mouse suggests that therapeutic or recreational cannabis use may be more distressing for immature primate neurons than inferred from experiments with rodents.

Cannabinoid receptor type 1 regulates sequential stages of migration and morphogenesis of neural crest cells and derivatives in chicken and frog embryos

“…However, overactivation of CB1R with ACEA prevented, or at least delayed, nerve projection in the majority of ophthalmic lobes of the trigeminal ganglia in chick embryos, as evidenced by a shorter ophthalmic lobe with nerve. This result is reminiscent of the aberrant nerve projection from the optic nerve in frog embryos treated with ACEA (Elul et al, 2022) or disoriented axonal processes from cortical neurons in the mouse and the Rhesus monkey (Morozov et al, 2020). AM251 treatment caused the trigeminal nerve to form more posteriorly than expected, closer to the otic pit.…”

Regional redistribution of CB1 cannabinoid receptors in human foetal brains with Down's syndrome and their functional modifications in Ts65Dn+/+ mice

“…Instead, we referred to ‘varicosities’, a morphological descriptor purely considering the shape of CB 1 R + structures. Nevertheless, ultrastructural data from the rodent and primate neocortex revealed CB 1 R expression in the somata of neurons radially migrating across the cortical plate [12]. The expression of CB 1 R at the early neuroblast phase is relevant to (endo‐)cannabinoid‐induced nucleokinesis [57], a key step of directional chemotaxis.…”

“…Here, we show that the temporal dynamics of CB 1 R expression is distinct in Down's syndrome: The appearance of CB 1 Rs is delayed, particularly during the early phase of brain development (first/second trimesters), and stays disproportionately high also at foetal periods when CB 1 R expression in controls becomes reduced. These pathogenic changes could provoke an imbalance of neurogenesis, radial cell migration [12] and morphogenesis leading to cortical delamination in Down's syndrome. We could not identify a morphological difference of CB 1 R + profiles in Down's syndrome, supporting that the time factor, but not compartmentalization, is a principal determinant of altered endocannabinoid signalling.…”

“…In contrast, the endocannabinoid family of small signal lipids serves as one of the guidance systems to define synapse localisation and selection during brain development. Herein, endocannabinoids can act in an autocrine/cellautonomous fashion when controlling neural progenitor proliferation through non-CB 1 R-mediated mechanisms [9][10][11][12]. Indeed, CB 1 R expression is seen as a feature of neurogenic commitment in vertebrates [13], with a marked increase in CB 1 R expression and responsiveness once neuroblasts leave their respective progenitor zones [14,15].…”

“…Because of its abundant expression, neocortical development is thought to rely on CB 1 Rs‐mediated endocannabinoid signalling. Upon synthesis and trans ‐Golgi maturation in neuronal somata [12], CB 1 Rs are rapidly transported on small vesicles along corticofugal axons [24]. The preferential axonal distribution of CB 1 Rs can thus steer directional growth decisions [14, 19].…”