Contribution of altered endocannabinoid system to overactive mTORC1 signaling in focal cortical dysplasia

Daniel García-Rincón, Javier Díaz-Alonso, Juan Paraíso-Luna, Zaira Ortega, José Aguareles, Adán De Salas-Quiroga, Cristina Jou, Inmaculada De Prada, Veronica Martinez-Cerdeno, Eleonora Aronica, Manuel Guzmán, María Ángeles Pérez-Jiménez, Ismael Galve-Roperh

Research output: Contribution to journalArticle

Abstract

Alterations of the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are causally involved in a subset of malformations of cortical development (MCDs) ranging from focal cortical dysplasia (FCD) to hemimegalencephaly and megalencephaly. These MCDs represent a frequent cause of refractory pediatric epilepsy. The endocannabinoid system -especially cannabinoid CB1 receptor-exerts a neurodevelopmental regulatory role at least in part via activation of mTORC1 signaling. Therefore, we sought to characterize the possible contribution of endocannabinoid system signaling to FCD. Confocal microscopy characterization of the CB1 receptor expression and mTORC1 activation was conducted in FCD Type II resection samples. FCD samples were subjected to single nucleotide polymorphism screening for endocannabinoid system elements, as well as CB1 receptor gene sequencing. Cannabinoid CB1 receptor levels were increased in FCD with overactive mTORC1 signaling. CB1 receptors were enriched in phospho-S6-positive cells including balloon cells (BCs) that co-express aberrant markers of undifferentiated cells and dysplastic neurons. Pharmacological regulation of CB1 receptors and the mTORC1 pathway was performed in fresh FCD-derived organotypic cultures. HU-210-evoked activation of CB1 receptors was unable to further activate mTORC1 signaling, whereas CB1 receptor blockade with rimonabant attenuated mTORC1 overactivation. Alterations of the endocannabinoid system may thus contribute to FCD pathological features, and blockade of cannabinoid signaling might be a new therapeutic intervention in FCD.

Original languageEnglish (US)
Article number1508
JournalFrontiers in Pharmacology
Volume9
Issue numberJAN
DOIs
StatePublished - Jan 1 2019

Fingerprint

Malformations of Cortical Development
Endocannabinoids
Cannabinoid Receptor CB1
rimonabant
Megalencephaly
mechanistic target of rapamycin complex 1
S 6
Cannabinoids
Phosphatidylinositol 3-Kinases
Confocal Microscopy
Single Nucleotide Polymorphism
Epilepsy
Pharmacology
Pediatrics
Neurons

Keywords

  • Cannabinoid
  • Cannabinoid
  • CB1 receptor
  • Corticogenesis
  • Malformation of cortical development
  • Mammalian target of rapamycin
  • MTORC1
  • Neural progenitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

García-Rincón, D., Díaz-Alonso, J., Paraíso-Luna, J., Ortega, Z., Aguareles, J., De Salas-Quiroga, A., ... Galve-Roperh, I. (2019). Contribution of altered endocannabinoid system to overactive mTORC1 signaling in focal cortical dysplasia. Frontiers in Pharmacology, 9(JAN), [1508]. https://doi.org/10.3389/fphar.2018.01508

Contribution of altered endocannabinoid system to overactive mTORC1 signaling in focal cortical dysplasia. / García-Rincón, Daniel; Díaz-Alonso, Javier; Paraíso-Luna, Juan; Ortega, Zaira; Aguareles, José; De Salas-Quiroga, Adán; Jou, Cristina; De Prada, Inmaculada; Martinez-Cerdeno, Veronica; Aronica, Eleonora; Guzmán, Manuel; Pérez-Jiménez, María Ángeles; Galve-Roperh, Ismael.

In: Frontiers in Pharmacology, Vol. 9, No. JAN, 1508, 01.01.2019.

Research output: Contribution to journalArticle

García-Rincón, D, Díaz-Alonso, J, Paraíso-Luna, J, Ortega, Z, Aguareles, J, De Salas-Quiroga, A, Jou, C, De Prada, I, Martinez-Cerdeno, V, Aronica, E, Guzmán, M, Pérez-Jiménez, MÁ & Galve-Roperh, I 2019, 'Contribution of altered endocannabinoid system to overactive mTORC1 signaling in focal cortical dysplasia', Frontiers in Pharmacology, vol. 9, no. JAN, 1508. https://doi.org/10.3389/fphar.2018.01508
García-Rincón D, Díaz-Alonso J, Paraíso-Luna J, Ortega Z, Aguareles J, De Salas-Quiroga A et al. Contribution of altered endocannabinoid system to overactive mTORC1 signaling in focal cortical dysplasia. Frontiers in Pharmacology. 2019 Jan 1;9(JAN). 1508. https://doi.org/10.3389/fphar.2018.01508
García-Rincón, Daniel ; Díaz-Alonso, Javier ; Paraíso-Luna, Juan ; Ortega, Zaira ; Aguareles, José ; De Salas-Quiroga, Adán ; Jou, Cristina ; De Prada, Inmaculada ; Martinez-Cerdeno, Veronica ; Aronica, Eleonora ; Guzmán, Manuel ; Pérez-Jiménez, María Ángeles ; Galve-Roperh, Ismael. / Contribution of altered endocannabinoid system to overactive mTORC1 signaling in focal cortical dysplasia. In: Frontiers in Pharmacology. 2019 ; Vol. 9, No. JAN.
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