Initiation of Behavioral Response to Antidepressants by Cholecystokinin Neurons of the Dentate Gyrus

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressant drugs, but the cellular and molecular mechanisms by which their therapeutic action is initiated are poorly understood. Here we show that serotonin 5-HT1B receptors in cholecystokinin (CCK) inhibitory interneurons of the mammalian dentate gyrus (DG) initiate the therapeutic response to antidepressants. In these neurons, 5-HT1B receptors are expressed presynaptically, and their activation inhibits GABA release. Inhibition of GABA release from CCK neurons disinhibits parvalbumin (PV) interneurons and, as a consequence, reduces the neuronal activity of the granule cells. Finally, inhibition of CCK neurons mimics the antidepressant behavioral effects of SSRIs, suggesting that these cells may represent a novel cellular target for the development of fast-acting antidepressant drugs. •DG CCK neurons are highly modulated by 5-HT via 5-HT2A and 5-HT1B receptors•Presynaptic 5-HT1BRs inhibit CCK GABA release and initiate the response to SSRIs•CCK neurons mediate the antidepressant effect through disinhibition of PV neurons•Chemogenetic inhibition of CCK neurons mimics the behavioral response to SSRIs Medrihan et al. show that the initial behavioral improvement induced by SSRIs in the DG starts with the inhibition of CCK neurons, which leads to a disinhibition of PV neurons and a reduced excitability of granule cells.