Cited by 96Cannabis and Cannabinoid ResearchAxon Guidance and Neuronal SignalingNeurogenesis and neuroplasticity mechanisms

Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

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Alpár, Alán, Tortoriello, Giuseppe, Calvigioni, Daniela, Niphakis, Micah J., Milenkovic, Ivan, Bakker, Joanne, Cameron, Gary A., Hanics, János +9 more·2014·Nature Communications

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.

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  • Pathway analyses based on cell type-specific significant DNAm changes associated with cannabis use implicated pathways such as the Slit-Robo signalling (granulocytes), the ErbB signalling pathway (T-cell) and pathways involved in DNA repair (B-cell).

    “Interestingly, the pathway analyses based on the cell type-specific significant DNAm changes associated with CU implicated pathways such as the Slit-Robo signalling (granulocytes) under the regulatory control of the endocannabinoid system during brain cortical development (Alpár et al., 2014), the ErbB signalling pathway (T-cell) and pathways involved in DNA repair (B-cell) (Clark et al., 2021).”

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Research works printed but not linked: 2

  1. [46]Berrendero F Sepe N Ramos JA Di Marzo V Fernandez-Ruiz JJ Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period Synapse 1999 33 181 191 10420166
  2. [55]Keimpema E Mackie K Harkany T Molecular model of cannabis sensitivity in developing neuronal circuits Trends Pharmacol. Sci 2011 32 551 561 21757242 PMC3159827

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Authors
Alpár, A., Tortoriello, G., Calvigioni, D., Niphakis, M. J., Milenkovic, I., Bakker, J., Cameron, G. A., Hanics, J., Morris, C. V., Fuzik, J., Kovacs, G. G., Cravatt, B. F., Parnavelas, J. G., Andrews, W. D., Hurd, Y. L., Keimpema, E., & Harkany, T.
Affiliations
  • Karolinska Institutet (SE)
  • Scripps Research Institute (US)
  • Medical University of Vienna (AT)
  • University of Aberdeen (GB)
  • Semmelweis University (HU)
  • Icahn School of Medicine at Mount Sinai (US)
  • University College London (GB)
Corresponding author
Harkany, Tibor
Venue
Nature Communications
Published
2014-07-17
Volume
5
Issue
1
Pages
4421-4421
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2030496268
Cited by
96
References
64
Citations by year
2026: 5 · 2025: 10 · 2024: 3 · 2023: 9 · 2022: 17 · 2021: 4 · 2020: 21 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 10 · 2014: 1
FWCI
4.37
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust (089775)
  • Karolinska Institutet
  • National Institute on Drug Abuse (F31DA031559, R01DA023214, R01DA030359, DA023214, DA030359)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
endocannabinoids, 2-arachidonoylglycerol, axon guidance, cortical development, corticofugal axons, CB1 receptor, CB2 receptor, oligodendrocyte differentiation, prenatal drug exposure, human fetal brain
MeSH terms
Roundabout Proteins, Slit Homolog 2 Protein, Animals, Arachidonic Acids, Axons, Brain, Cells, Cultured, Corpus Callosum, Female, Glycerides, Humans, Immunohistochemistry, Male, Nerve Tissue Proteins, Pregnancy, Receptors, Immunologic, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Receptor, Cannabinoid, CB1, Mice, Endocannabinoids

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