The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reductio...

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Bibliographic Details
Authors: Costas Insúa, Carlos, Hermoso López, Alba, Moreno, Estefanía, Montero Fernández, Carlos, Álvaro Blázquez, Alicia, Maroto, Irene, Sánchez Ruíz, Andrea, Díez Alarcia, Rebeca, Blázquez Ortiz, Cristina, Morales, Paula, Canela, Enric, Casadó, Vicent, Urigüen, Leyre, Perea, Gertrudis, Bellocchio, Luigi, Rodríguez Crespo, José Ignacio, Guzmán Pastor, Manuel
Format: article
Publication Date:2024
Country:España
Institution:Universidad Complutense de Madrid (UCM)
Repository:Docta Complutense
Language:English
OAI Identifier:oai:docta.ucm.es:20.500.14352/114201
Online Access:https://hdl.handle.net/20.500.14352/114201
Access Level:Open access
Keyword:577.1
Cannabinoid
Cereblon
Hippocampus
Memory
Rimonabant
Biología
Ciencias
24 Ciencias de la Vida
2490 Neurociencias
2403 Bioquímica
Description
Summary:Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligaseindependent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiencylinked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

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