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.