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

The type-1 cannabinoid receptor (CB(1)R) 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 CB(1)R 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 CB(1)R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB(1)R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB(1)R-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 CB(1)R that hampers CB(1)R-mediated effects on hippocampal circuit function.