Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

Alán Alpár, Giuseppe Tortoriello, Daniela Calvigioni, Micah J. Niphakis, Ivan Milenkovic, Joanne Bakker, Gary A. Cameron, János Hanics, Claudia V. Morris, János Fuzik, Gabor G. Kovacs, Benjamin F. Cravatt, John G. Parnavelas, William D. Andrews, Yasmin L. Hurd, Erik Keimpema and Tibor Harkany ()
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Alán Alpár: Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
Giuseppe Tortoriello: Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
Daniela Calvigioni: Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
Micah J. Niphakis: The Scripps Research Institute
Ivan Milenkovic: Institute of Neurology, Medical University of Vienna
Joanne Bakker: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria
Gary A. Cameron: Institute of Medical Sciences, Liquid Chromatography-Mass Spectrometry Section, University of Aberdeen
János Hanics: Histology and Embryology, Semmelweis University
Claudia V. Morris: Icahn School of Medicine at Mount Sinai
János Fuzik: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria
Gabor G. Kovacs: Institute of Neurology, Medical University of Vienna
Benjamin F. Cravatt: The Scripps Research Institute
John G. Parnavelas: University College London
William D. Andrews: University College London
Yasmin L. Hurd: Icahn School of Medicine at Mount Sinai
Erik Keimpema: Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden
Tibor Harkany: Karolinska Institutet, Scheeles väg 1:A1, SE-17177 Stockholm, Sweden

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5421

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