RT Journal Article
T1 Contribution of Altered Endocannabinoid System to Overactive mTORC1 Signaling in Focal Cortical Dysplasia
A1 García Rincón, Daniel
A1 Díaz Alonso, Javier
A1 Paraíso Luna, Juan
A1 Otega, Zaira
A1 Aguareles Gorines, José
A1 Salas Quiroga, Adán de
A1 Jou, Cristina
A1 Prada, Inmaculada de
A1 Martínez Cerdeño, Verónica
A1 Aronica, Eleonora
A1 Guzmán, Manuel
A1 Pérez-Jiménez, María Ángeles
A1 Galve Roperh, Ismael
AB 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.
PB Frontiers Media
SN 1663-9812
YR 2019
FD 2019-01
LK https://hdl.handle.net/20.500.14352/13503
UL https://hdl.handle.net/20.500.14352/13503
LA eng
NO Unión Europea. H2020
NO Ministerio de Economía y Competitividad (MINECO)/FEDER
NO Instituto de Salud Carlos III
NO Ministerio de Educación, Cultura y Deporte (MECD)
NO Fundación Tatiana Pérez de Guzmán el Bueno
DS Docta Complutense
RD 11 abr 2025