The Role of Cannabinoidergic System in Prenatal Neurodevelopment

The cannabinoidergic system acquired a reputation as the most abundant G-protein coupled receptor in the CNS that acts as retrograde modulator of neurotransmitter release. Recently, endocannabinoids (ECBs) have been highlighted as neurodevelopmental signaling cues that exert a regulatory role in brain development. The interruption in ECB system elements (including receptors and enzymes of synthesis and degradation) in the developing brain is in relation with postnatal CNS pathophysiology. The rapid rates of ECB synthesis/degradation reveal the existence of a dynamically regulated ECB tone during the active neurogenesis. The cannabinoid CB1 receptor is expressed from very early stages of embryonic development, even before the appearance of the neural tube and ectoderm development. CB1 is present in trophoblast stem cells and its deletion results in reduced cell proliferation and differentiation that is followed by aberrant formation of placenta and compromised embryo implantation. In addition to CB1 receptor expression, the other cannabinoid receptor, the CB2 receptor, is also present in the inner cell mass, and is involved in embryonic stem-derived hematopoietic cell proliferation and differentiation. In mammals, CB1 receptor expression is characterized by its abundant levels in white matter areas (where the axons of neural cells are present), with their levels progressively increasing from prenatal stages to adulthood in grey matter areas (where mostly occupied by neural cell bodies and dendrites) during neural development. The expression of CB1 receptor during the development occurs in active neurogenesis and axonal migration and prior to the synaptic maturation and neuronal activity. Therefore, the action of CB1 receptors on neurodevelopment is likely to be independent of their regulatory role of neurotransmitter release and neuronal activity. At embryonic stage and during cortical development, CB1 receptors are present in pioneer neurons which develop cortical plate. At these stages, the CB1 receptor is also present in the hippocampus. Later, CB1 receptors are heterogeneously distributed through cortical layers and the hippocampus, in both excitatory glutamatergic projection neurons and GABAergic interneurons. In human fetal brain, there is growing evidence of CB1 receptor expression throughout the cerebral cortex, hippocampus, caudate nucleus, putamen and cerebellum. High densities of CB1 receptors are detected during the prenatal development in brain areas that are practically devoid of these receptors later in the adult brain. The early expression and function of the cannabinoid receptors during CNS development and its transient localization in prenatal stages suggest a specific role of the ECB system in human brain development, with potential implications in neuropsychiatric disorders. The two putative ECBs, anandamide (AEA) and 2-arachidonoylglycerol (2AG) can act in an autocrine or paracrine manner on neural progenitors. The ECB system is initially involved in axonal growth but is later redistributed to dendrites where it plays the retrograde modulatory role in neurotransmission. During the cortical and retinal development, ECB production participates in axon guidance and neurite outgrowth. The regulatory role of the CB1 receptor in neuronal generation and maturation in the embryonic brain is preserved in the neurogenic niches of the adult brain. Neural progenitors in adult neurogenic brain areas also express the CB1 receptor and produce ECB ligands. CB1 receptors are expressed in neural progenitor cells of the subgranular and subventricular zones, in which they drive progenitor proliferation and neural differentiation in adult brain. Therefore, the neurodevelopmental role of the ECBs is continued in the mature nervous system. Altered cannabinoid signaling (i.e. either hyperor hypo-function of Copyright © 2013 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services Iranian Journal of Pharmaceutical Research (2013), 12 (2): 257-259