Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain

Abstract

Previous evidence suggests that the endogenous cannabinoid system emerges relatively early during brain development in the rat. However, the pre- and postnatal pattern of appearance of CB1 cannabinoid receptors in humans has not been analysed in detail. Furthermore, there is a complete lack of information about the functional ability of these proteins to activate signal transduction mechanisms during human development. In the present study we have explored CB1 receptor expression throughout the different areas of the developing human brain by [3H]CP55 940 autoradiography. We have also assessed CB1 functional coupling to G proteins during brain development by agonist-stimulated [35S]GTPgammaS autoradiography in the same cases. Our results indicate a significant density of cannabinoid receptors at 19 weeks' gestation in the same areas that contain these receptors in the adult human brain. Autoradiographic levels of CB1 receptors in these structures seem to increase progressively from early prenatal stages to adulthood. Interestingly, high densities of cannabinoid receptors have also been detected during prenatal development in fibre-enriched areas that are practically devoid of them in the adult brain. In parallel with these data, we have found that brain cannabinoid receptors are functionally coupled to signal transduction mechanisms from early prenatal stages. This early pattern of expression of functionally active cannabinoid receptors, along with the transient and atypical localization of these proteins in white matter areas during the prenatal stages, suggest an specific role of the endocannabinoid system in the events related to human neural development.

Endocannabinoid functions controlling neuronal specification during brain development

“…Similar CB1R mRNA expression patterns have been reported during human pre-and postnatal CNS development by in situ hybridization (Wang et al, 2003). Pharmacological studies indicate the functionality of CB1Rs in embryonic neural tissues since WIN55212-2, a cannabinoid receptor agonist, significantly stimulated [ 35 S]GTPγS binding in both rodent and human brains (Mato et al, 2003;Wang et al, 2003).…”

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

“…Thus, CB1 receptors are detected at week 14 of gestation in the human embryo and, after 6 weeks, selective expression of CB1 receptor is recorded in the limbic area CA of the hippocampus and in the amygdale [94] . Consistent with the previous studies in rat models [92] , a progressive increase in the concentration of CB1 receptor is found in most human brain regions (frontal cortex, hippocampus, basal ganglia and cerebellum) from the fetal period to adulthood, with the CB1 receptors being functionally active at all stages of development [95] .…”

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…The expression and functionality of the ECB system has also been characterized in human brain development [23,24]. In human foetal brain, in situ hybridization and binding assays evidence a heterogeneous pattern of CB 1 receptor expression with preferential limbic expression and high levels throughout the cerebral cortex, hippocampus, caudate nucleus, putamen and cerebellum.…”