Loss of Cannabinoid CB1 Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility.
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.
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),  and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Javier
J
Díaz-Alonso
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),  and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain.
Adán
A
de Salas-Quiroga
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),  and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain.
Juan
J
Paraíso-Luna
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain.
Daniel
D
García-Rincón
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.|Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ, Brazil.
Patricia P
PP
Garcez
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.
Maddy
M
Parsons
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),  and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain.
Clara
C
Andradas
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),  and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Instituto de Investigación Sanitaria Hospital 12 de Octubre, 28041 Madrid, Spain.
Cristina
C
Sánchez
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW7 1AA, UK.
François
F
Guillemot
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),  and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain.
Manuel
M
Guzmán
Department of Biochemistry and Molecular Biology I, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), and Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, 28040 Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28049 Madrid, Spain.
Ismael
I
Galve-Roperh
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000378:metabolism / Q000473:pathology; D018274:Electroporation; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D017403:In Situ Hybridization; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010433:Pentylenetetrazole; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency* / Q000235:genetics; D012640:Seizures / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C578453:CNR1 protein, mouse; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D020742:rhoA GTP-Binding Protein; D010433:Pentylenetetrazole
endocannabinoid system; epileptogenesis; radial migration; small GTPases; subcortical band heterotopia