Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

Nat Commun. 2014 Jul 17;5:4421. doi: 10.1038/ncomms5421.

Abstract

Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / pharmacology
  • Axons / drug effects
  • Axons / metabolism
  • Brain / drug effects
  • Brain / embryology*
  • Brain / metabolism*
  • Cells, Cultured
  • Corpus Callosum / drug effects
  • Corpus Callosum / embryology
  • Corpus Callosum / metabolism
  • Endocannabinoids / pharmacology*
  • Female
  • Glycerides / pharmacology
  • Humans
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Pregnancy
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*

Substances

  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptor, Cannabinoid, CB1
  • Receptors, Immunologic
  • roundabout protein
  • glyceryl 2-arachidonate
  • Slit homolog 2 protein