The endocannabinoid (eCB) system is an ensemble of metabolic enzymes, endocannabinoids, and receptors that detect their presence and initiate a cascade of chemical responses. The components of the eCB can be found throughout the entire body, where they play a myriad of regulatory functions.
Of special interest is the regulation of neural development and neurogenesis. These processes are among the least known aspects of our biology, and the elucidation of the eCB role in them could have tremendous impact in terms of scientific understanding of normal and abnormal neuronal development and on the creation of novel treatments to fight the latter.
We know that the eCB system is already active in the early stages of neuronal development and retains an important role during adulthood. In the first stages, the eCB system regulates the specification and proliferation of neuronal and glial cells and, later, it modulates neuronal maturation and plasticity. A comprehensive review of these functions has been published by Galve-Roperh and colleagues from the Madrid Complutense University (link).
The authors mention that cannabinoid type 1 (CB1) receptors are present in the body from the two-cell stage of the embryo, whereas CB2 receptors are already present at the one-cell stage. Endocannabinoids can also be found early on, with 2-AG being most abundant in the embryo and Anandamide levels peaking at birth. Among other roles in uterus plantation and general cell regulation, the eCB plays a central role in neural development and regulation.
The first evidence of this came from the finding that during the embryonic stages, CB1 receptors are quite abundant in white matter areas of the brain, whereas during development, CB1 receptors become increasingly more present in the grey areas. Importantly, this transition correlates strongly with neural differentiation, which suggests a role of the eCB system in this process.
In mice that were genetically engineered to lack CB1 receptors, researchers found a smaller proliferation of neural progenitor cells (the ones that lead to neurons) in key areas of the brain. On the contrary, when endocannabinoid levels were increased there was an enhanced proliferation of these cells. In addition, CB1 receptors regulate the formation of neural projections and synapses between neurons. All these results have been replicated with the administration of CB1 agonists and antagonists (including THC in some studies), which reinforces the role of the eCB in these processes.
CB2 receptors play a less clear role in neuronal development. Researchers found these receptors to be relatively abundant in neural progenitor and stem cells, but absent in fully fledged neurons. When CB2 receptors were genetically removed or chemically manipulated, similar results to those of CB1 manipulations were found. Some researchers have proposed that CB2 receptors may be specifically involved in critical situations, such as active stages of brain development, neuronal loss following brain injury, and neurodegenerative disorders. Finally, an indirect mechanism of action of CB2 receptors in neurogenesis has been studied. Via immune cell activity, these receptors reduce brain inflammation, which in turn prevents the inhibition of neurogenesis.
For Galve-Roperh and colleagues, the newly found role of the eCB system in neural development underscores the extreme vulnerability of the developing brain to the exposure of cannabinoids. Moreover, it suggests an involvement in the etiology of psychopathology. While THC and other cannabinoids do not seem to be neurotoxic, they could affect cognitive and emotional processes by interfering with the fine regulation of neural activity. Supporting evidence comes from studies showing that endocannabinoid and cannabinoid receptor levels are altered in depressed patients and in animals subjected to maternal deprivation and social isolation.
On the other hand, the ability of the eCB system to regulate neuronal survival and plasticity could open the door to new interventions in neuronal disorders. In agreement with this is the fact that cannabinoid agonists reduce depressive and anxiety symptoms in animal models. There is also accumulating evidence showing that these effects are mediated by neurogenic processes. In a 2013 study, Dr. Alline Campos and collaborators demonstrated that CBD increased hippocampal neurogenesis and produced anxiolytic effects, and that when the former was prevented the latter vanished. Thus it seems that cannabinoid-mediated neurogenesis in adult rats is related to its anxiolytic effects.
While research of the neuronal regulation of the eCB system has exploded in the last decade, our understanding of it is still in its early stages. Undoubtedly, much will be found in the years to come and, hopefully, this knowledge will prove fruitful in the understanding and management of the developmental, psychiatric, and neurodegenerative disorders that haunt so many people worldwide.