Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19115-20. doi: 10.1073/pnas.0509494102. Epub 2005 Dec 15.


In utero exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Delta(9)-THC-induced cognitive impairments, the neuronal basis of Delta(9)-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB(1) cannabinoid receptor (CB(1)R) 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 Delta(9)-THC stimulation of CB(1)Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB(1)R 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.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • Brain-Derived Neurotrophic Factor / physiology
  • Cannabinoid Receptor Modulators / physiology*
  • Cell Differentiation
  • Cell Movement
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / embryology
  • Chemotaxis
  • Dose-Response Relationship, Drug
  • Electrophysiology
  • Endocannabinoids*
  • Hippocampus / metabolism
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Hybridization
  • Interneurons / metabolism*
  • Morphogenesis
  • Neuronal Plasticity
  • Neurons / metabolism*
  • Rabbits
  • Rats
  • Receptor, trkB / metabolism*
  • Receptors, Cannabinoid / metabolism
  • Receptors, Drug / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Substance-Related Disorders
  • Time Factors
  • Transcriptional Activation
  • Transfection
  • gamma-Aminobutyric Acid / metabolism
  • src-Family Kinases / metabolism


  • Brain-Derived Neurotrophic Factor
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Receptors, Cannabinoid
  • Receptors, Drug
  • gamma-Aminobutyric Acid
  • Receptor, trkB
  • src-Family Kinases