Loss of Cannabinoid CB1 Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility

Cereb Cortex. 2017 Nov 1;27(11):5303-5317. doi: 10.1093/cercor/bhw309.


Neuronal migration is a fundamental process of brain development, and its disruption underlies devastating neurodevelopmental disorders. The transcriptional programs governing this process are relatively well characterized. However, how environmental cues instruct neuronal migration remains poorly understood. Here, we demonstrate that the cannabinoid CB1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB1 receptor alters neuronal morphology and impairs radial migration. Consequently, CB1 siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB1 deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB1 receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB1 receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain.

Keywords: endocannabinoid system; epileptogenesis; radial migration; small GTPases; subcortical band heterotopia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / physiology*
  • Cerebral Cortex / abnormalities*
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Disease Models, Animal
  • Disease Susceptibility / metabolism
  • Disease Susceptibility / pathology
  • Electroporation
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • In Situ Hybridization
  • Mice, Transgenic
  • Microscopy, Confocal
  • Pentylenetetrazole
  • Pyramidal Cells / metabolism*
  • Pyramidal Cells / pathology
  • RNA, Small Interfering
  • Receptor, Cannabinoid, CB1 / deficiency*
  • Receptor, Cannabinoid, CB1 / genetics
  • Seizures / metabolism*
  • Seizures / pathology
  • Tissue Culture Techniques
  • rhoA GTP-Binding Protein / antagonists & inhibitors
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism


  • CNR1 protein, mouse
  • RNA, Small Interfering
  • Receptor, Cannabinoid, CB1
  • rhoA GTP-Binding Protein
  • Pentylenetetrazole