Costas-Insua C, Hermoso-López A,... , Rodríguez-Crespo I, Guzmán M. The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls
EMBO Mol Med. 2024
"This study unveils an unprecedented molecular process involved in the amnesic effect of cannabis"- Dr. Manuel Guzmán-
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 ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.
Why do you highlight this publication?
It is well known that cannabis acts on our brain by engaging the cannabinoid CB1 receptor (CB1R). In this study, we show that a protein called cereblon interacts specifically with the cytoplasmatic domain of CB1R in memory circuits of the mouse hippocampus. As a consequence, the amnesic functions of the receptor are remarkably impaired. Moreover, we generated a mouse model of cereblon deficiency-associated intellectual disability and found that the memory shortfalls shown by these animals are due to an overactivation of CB1R in the aforementioned neuronal circuits. This report provides a new conceptual framework to understand the molecular basis of a well-known effect of cannabis use, namely amnesia, and put forward the use of CB1R-selective antagonists to improve memory function in patients with an orphan disease as cereblon deficiency-associated intellectual disability.
Publication commented by:
Dr. Manuel Guzmán
Department of Biochemistry and Molecular Biology at Complutense University of Madrid
NEURODEGENERATIVE DISEASES: PATHOGENIC MECHANISMS Group-IRYCIS
