Cholecystokinin (CCK) enables long-term potentiation of the excitatory circuit. Here, we investigated its role in the neuroplasticity of the inhibitory synapses using a model in which activation of GABA neurons suppressed neuronal responses to the forthcoming auditory stimulus in the neocortex. The suppression was enhanced only after high-frequency laser stimulation (HFLS) of GABAergic neurons optogenetically. This potentiation was abolished in CCK-knockout (KO) mice. Inhibitory postsynaptic current in the pyramidal neuron was potentiated after the HFLS of CCK-GABA neurons, but not PV neurons.

Interestingly, this effect was not mediated by known CCK receptors, as CCK-1/2R-KO mice still showed the potentiation of inhibition after the HFLS of CCK-GABA neurons. We found that GPR173/SREB3 shares a high similarity in the extramembrane structures with CCK1R and 2R. GPR173 had an affinity of EC₅₀ = 3.23 nM to CCK8s, similarly to CCK2R. GPR173 colocalized with CCK-GABA terminals and GABAar. Notably, an antagonist to GPR173 blocked the HFLS-induced potentiation of inhibition. We concluded that GPR173 is a novel CCK receptor that mediates the activity of CCK in potentiating the inhibitory synapses.