Irene B. Maroto, Carlos Costas-Insua, Coralie Berthoux, Estefanía Moreno, Andrea Ruiz-Calvo...Ismael Galve-Roperh...Manuel Guzmán. Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43

Nat Commun. 2023

"This study unveils an unprecedented molecular process involved in the anti-convulsant effect of cannabinoids" - Dr. Manuel Guzmán Pastor-


The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function.

Why do you highlight this publication?

It is well known that cannabis impacts our brain by engaging the cannabinoid CB1 receptor (CB1R). In this study, we show that a protein called GAP43, when activated, interacts specifically with CB1R in a pro-epileptogenic circuit of the mouse hippocampus. As a consequence, the synaptic functions of the receptor are remarkably impaired. This finding provides a new conceptual framework to understand the molecular basis of a well-known clinical application of cannabinoids, namely their anti-convulsant activity.

Publication commented by:

Dr. Manuel Guzmán

Faculty of Biological Sciences. Madrid Complutense University


Immunofluorescence image of the whole mouse hippocampal formation (CB1R in green, GAP43 in red, nuclei/DAPI in blue). Note the strong co-localization of CB1R and GAP43 in the inner molecular layer of the dentate gyrus.
Altmetrics, May 2023

Documents and links