Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43

Irene B. Maroto, Carlos Costas-Insua, Coralie Berthoux, Estefanía Moreno, Andrea Ruiz-Calvo, Carlos Montero-Fernández, Andrea Macías-Camero, Ricardo Martín, Nuria García-Font, José Sánchez-Prieto, Giovanni Marsicano, Luigi Bellocchio, Enric I. Canela, Vicent Casadó, Ismael Galve-Roperh, Ángel Núñez, David Fernández de Sevilla, Ignacio Rodríguez-Crespo, Pablo E. Castillo and Manuel Guzmán ()
Additional contact information
Irene B. Maroto: Complutense University
Carlos Costas-Insua: Complutense University
Coralie Berthoux: Albert Einstein College of Medicine
Estefanía Moreno: University of Barcelona
Andrea Ruiz-Calvo: Complutense University
Carlos Montero-Fernández: Complutense University
Andrea Macías-Camero: Complutense University
Ricardo Martín: Complutense University
Nuria García-Font: Complutense University
José Sánchez-Prieto: Complutense University
Giovanni Marsicano: Physiopathologie de la Plasticité Neuronale, U1215
Luigi Bellocchio: Physiopathologie de la Plasticité Neuronale, U1215
Enric I. Canela: University of Barcelona
Vicent Casadó: University of Barcelona
Ismael Galve-Roperh: Complutense University
Ángel Núñez: Autónoma University
David Fernández de Sevilla: Autónoma University
Ignacio Rodríguez-Crespo: Complutense University
Pablo E. Castillo: Albert Einstein College of Medicine
Manuel Guzmán: Complutense University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38026-2

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