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Miswiring the brain: Δ9‐tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin‐2 degradation pathway

Giuseppe Tortoriello, Claudia V Morris, Alan Alpar, Janos Fuzik, Sally L Shirran, Daniela Calvigioni, Erik Keimpema, Catherine H Botting, Kirstin Reinecke, Thomas Herdegen, Michael Courtney, Yasmin L Hurd, Tibor Harkany

Author Affiliations

  1. Giuseppe Tortoriello1,
  2. Claudia V Morris2,
  3. Alan Alpar1,
  4. Janos Fuzik1,3,
  5. Sally L Shirran4,
  6. Daniela Calvigioni1,
  7. Erik Keimpema1,3,
  8. Catherine H Botting4,
  9. Kirstin Reinecke5,
  10. Thomas Herdegen5,
  11. Michael Courtney6,
  12. Yasmin L Hurd2 and
  13. Tibor Harkany*,1,3
  1. 1Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  2. 2Icahn School of Medicine at Mount Sinai, New York, NY, USA
  3. 3Department of Molecular Neurosciences, Center for Brain Research Medical University of Vienna, Vienna, Austria
  4. 4School of Chemistry University of St. Andrews, St Andrews, UK
  5. 5Institute of Experimental and Clinical Pharmacology University Hospital Schleswig‐Holstein, Kiel, Germany
  6. 6A. I. Virtanen Institute University of Eastern Finland, Kuopio, Finland
  1. *Corresponding author. Tel: +46 8 524 87656; Fax: +46 8 341 960; E‐mail: Tibor.Harkany{at}ki.se

Abstract

Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9‐tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor‐driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC‐sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin‐2, a microtubule‐binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis‐exposed fetuses, defining SCG10 as the first cannabis‐driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c‐Jun N‐terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.

See also: L Cristino & V Di Marzo (April 2014)

Synopsis

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Δ9‐tetrahydrocannabinol (THC), the major psychoactive component from cannabis, is shown to activate a molecular cascade modulating SCG10/stathmin‐2 availability and function, thus inducing cytoskeletal modifications in fetal neurons.

  • In vivo experiments demonstrate that THC disrupts endocannabinoid signaling and acts as a functional antagonist in the fetal brain.

  • C‐Jun terminal kinase links CB1 cannabinoid receptor and SCG10/stathmin‐2 phosphorylation and degradation.

  • Maternal cannabis smoking reduces SCG10/stathmin‐2 mRNA and protein expression in human fetal brains, identifying SCG10/stathmin‐2 as a key molecular effector mediating adverse cannabis effects.

EMBO Journal (2014) 33, 668–685

  • Received June 19, 2013.
  • Revision received November 26, 2013.
  • Accepted December 10, 2013.

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