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

Javier Díaz-Alonso; Adán De Salas-Quiroga; Juan Paraíso-Luna; Daniel García-Rincón; Patricia P. Garcez; Maddy Parsons; Clara Andradas; Cristina Sánchez; François Guillemot; Manuel Guzmán; Ismael Galve-Roperh

doi:10.1093/cercor/bhw309

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

Javier Díaz-Alonso^*, Adán De Salas-Quiroga, Juan Paraíso-Luna, Daniel García-Rincón, Patricia P. Garcez, Maddy Parsons, Clara Andradas, Cristina Sánchez, François Guillemot, Manuel Guzmán, Ismael Galve-Roperh

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

Abstract

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 CB 1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB 1 receptor alters neuronal morphology and impairs radial migration. Consequently, CB 1 siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB 1 deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB 1 receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB 1 receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain.

Original language	English
Pages (from-to)	5303-5317
Number of pages	15
Journal	Cerebral Cortex
Volume	27
Issue number	11
Early online date	5 Oct 2016
DOIs	https://doi.org/10.1093/cercor/bhw309
Publication status	Published - 1 Nov 2017

Keywords

endocannabinoid system
epileptogenesis
radial migration
small GTPases
subcortical band heterotopia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/cercor/bhw309

Cite this

Díaz-Alonso, J., De Salas-Quiroga, A., Paraíso-Luna, J., García-Rincón, D., Garcez, P. P., Parsons, M., Andradas, C., Sánchez, C., Guillemot, F., Guzmán, M., & Galve-Roperh, I. (2017). Loss of Cannabinoid CB₁ Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility. Cerebral Cortex, 27(11), 5303-5317. https://doi.org/10.1093/cercor/bhw309

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abstract = "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 CB 1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB 1 receptor alters neuronal morphology and impairs radial migration. Consequently, CB 1 siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB 1 deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB 1 receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB 1 receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain.",

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Díaz-Alonso, J, De Salas-Quiroga, A, Paraíso-Luna, J, García-Rincón, D, Garcez, PP, Parsons, M, Andradas, C, Sánchez, C, Guillemot, F, Guzmán, M & Galve-Roperh, I 2017, 'Loss of Cannabinoid CB₁ Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility', Cerebral Cortex, vol. 27, no. 11, pp. 5303-5317. https://doi.org/10.1093/cercor/bhw309

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AU - Díaz-Alonso, Javier

AU - De Salas-Quiroga, Adán

AU - Paraíso-Luna, Juan

AU - García-Rincón, Daniel

AU - Garcez, Patricia P.

AU - Parsons, Maddy

AU - Andradas, Clara

AU - Sánchez, Cristina

AU - Guillemot, François

AU - Guzmán, Manuel

AU - Galve-Roperh, Ismael

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AB - 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 CB 1 receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB 1 receptor alters neuronal morphology and impairs radial migration. Consequently, CB 1 siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB 1 deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB 1 receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB 1 receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain.

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