Cannabinoid receptors 1 (CB1) are widely expressed in the central nervous system and have been recognized as regulators of adult plasticity and brain development, including wiring of neuronal connections. CB1 receptors are targets of both endocannabinoids and phytocannabinoids (e.g., Cannabis-derived D9- THC) and it has been reported that children exposed in utero to cannabis present neurobehavioral and cognitive impairments1. In the zebrafish embryo, previous data showed that CB1 receptor knockdown causes abnormal axonal growth in forebrain areas, characterized by failure in fasciculation of axonal tracts2. Since this area is rich in Gonadotropin Releasing Hormone (GnRH) and Agouti-related peptide (AgRP) expressing fibers, the aim of this study was to assess whether pharmacological modulation of CB1 could modify GnRH and AgRP axonal pathfinding during zebrafish early neurodevelopment. Immunofluorescence analysis suggested that, during early developmental stages, CB1 is expressed in forebrain areas where both GnRH3 and AgRP1 fibers are present and co-localize with GnRH3-expressing axons. Transgenic GnRH3:EGFP and AgRP1:mCherry zebrafish embryos treated with different CB1 ligands (agonist, antagonist and reverse agonist) showed axon misrouting and abnormal pathfinding of both GnRH3 and AgRP1 fibers in the anterior commissure. Similar phenotypes were obtained by morpholinomediated CB1 knockdown. CB1 pharmacological modulation influenced CB1, GnRH3 and AgRP1 expression levels, as well as the expression of some genes involved in axonal growth and cell migration, such as Stmn2a/b, Negr1 and Sez6a/b. Overall, these results indicate that CB1 act during development as regulators of axonal pathfinding on GnRH and AgRP neurons. Moving from the animal model to humans, the implications of these results are important in the contest of prenatal exposure to Cannabis. References 1. Calvigioni D, et al. Eur Child Adolesc Psychiatry 2014;23:931-41. 2. Watson S, et al. Mol Cell Neurosci 2008;38:89-97.
INTERFERENCE WITH THE CANNABINOID RECEPTOR CB1 AFFECTS GNRH AND AGRP1 NEURONAL DEVELOPMENT IN ZEBRAFISH EMBRYOS
G. Zuccarini;E. Cottone;I. D’Atri;Y. Gothilf;G. R. Merlo;P. Bovolin
2019-01-01
Abstract
Cannabinoid receptors 1 (CB1) are widely expressed in the central nervous system and have been recognized as regulators of adult plasticity and brain development, including wiring of neuronal connections. CB1 receptors are targets of both endocannabinoids and phytocannabinoids (e.g., Cannabis-derived D9- THC) and it has been reported that children exposed in utero to cannabis present neurobehavioral and cognitive impairments1. In the zebrafish embryo, previous data showed that CB1 receptor knockdown causes abnormal axonal growth in forebrain areas, characterized by failure in fasciculation of axonal tracts2. Since this area is rich in Gonadotropin Releasing Hormone (GnRH) and Agouti-related peptide (AgRP) expressing fibers, the aim of this study was to assess whether pharmacological modulation of CB1 could modify GnRH and AgRP axonal pathfinding during zebrafish early neurodevelopment. Immunofluorescence analysis suggested that, during early developmental stages, CB1 is expressed in forebrain areas where both GnRH3 and AgRP1 fibers are present and co-localize with GnRH3-expressing axons. Transgenic GnRH3:EGFP and AgRP1:mCherry zebrafish embryos treated with different CB1 ligands (agonist, antagonist and reverse agonist) showed axon misrouting and abnormal pathfinding of both GnRH3 and AgRP1 fibers in the anterior commissure. Similar phenotypes were obtained by morpholinomediated CB1 knockdown. CB1 pharmacological modulation influenced CB1, GnRH3 and AgRP1 expression levels, as well as the expression of some genes involved in axonal growth and cell migration, such as Stmn2a/b, Negr1 and Sez6a/b. Overall, these results indicate that CB1 act during development as regulators of axonal pathfinding on GnRH and AgRP neurons. Moving from the animal model to humans, the implications of these results are important in the contest of prenatal exposure to Cannabis. References 1. Calvigioni D, et al. Eur Child Adolesc Psychiatry 2014;23:931-41. 2. Watson S, et al. Mol Cell Neurosci 2008;38:89-97.
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