Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

Paul Berghuis, Marton B. Dobszay, Xinyu Wang, Sabrina Spano, Fernanda Ledda, Kyle M. Sousa, Gunnar Schulte, Patrik Ernfors, Ken Mackie, Gustavo Paratcha, Yasmin L. Hurd, Tibor Harkany

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

Abstract

In utero exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Δ9-THC-induced cognitive impairments, the neuronal basis of Δ9-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB1 cannabinoid receptor (CB1R) on cholecystokinin-expressing interneurons induces chemotaxis that is additive with brain-derived neurotrophic factor (BDNF)-induced interneuron migration. We find that Src kinase-dependent TrkB receptor transactivation mediates endocannabinoid (eCB)-induced chemotaxis in the absence of BDNF. Simultaneously, eCBs suppress the BDNF-dependent morphogenesis of interneurons, and this suppression is abolished by Src kinase inhibition in vitro. Because sustained prenatal Δ9-THC stimulation of CB1Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB1R activity governs proper interneuron placement and integration during corticogenesis. Moreover, eCBs use TrkB receptor-dependent signaling pathways to regulate subtype-selective interneuron migration and specification.

Original languageEnglish
Pages (from-to)19115-19120
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number52
DOIs
StatePublished - 27 Dec 2005
Externally publishedYes

Keywords

  • Corticogenesis
  • Drug abuse
  • Neurotrophin

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