Interference with the cannabinoid receptor CB1R results in miswiring of GnRH3 and AgRP1 axons in zebrafish embryos

Giulia Zuccarini, Ilaria D’atri, Erika Cottone, Ken Mackie, Inbal Shainer, Yoav Gothilf, Paolo Provero, Patrizia Bovolin*, Giorgio Roberto Merlo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The G protein-coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and their endocannabinoid (eCBs) ligands, have been implicated in several aspects of brain wiring during development. Here we aim to assess whether interfering with CB1R affects development, neuritogenesis and pathfinding of GnRH and AgRP neurons, forebrain neurons that control respectively reproduction and appetite. We pharmacologically and genetically interfered with CB1R in zebrafish strains with fluorescently labeled GnRH3 and the AgRP1 neurons. By applying CB1R antagonists we observed a reduced number of GnRH3 neurons, fiber misrouting and altered fasciculation. Similar phenotypes were observed by CB1R knockdown. Interfering with CB1R also resulted in a reduced number, misrouting and poor fasciculation of the AgRP1 neuron’s axonal projections. Using a bioinformatic approach followed by qPCR validation, we have attempted to link CB1R functions with known guidance and fasciculation proteins. The search identified stathmin-2, a protein controlling microtubule dynamics, previously demonstrated to be coexpressed with CB1R and now shown to be downregulated upon interference with CB1R in zebrafish. Together, these results raise the likely possibility that embryonic exposure to low doses of CB1R-interfering compounds could impact on the development of the neuroendocrine systems controlling sexual maturation, reproduction and food intake.

Original languageEnglish
Article number168
JournalInternational Journal of Molecular Sciences
Volume21
Issue number1
DOIs
StatePublished - Jan 2020

Keywords

  • AgRP
  • Axon guidance
  • Cannabinoid receptor
  • GnRH
  • Neuroendocrine
  • Stathmin
  • Zebrafish

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