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

Abstract

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.

Tissue‐ and cell‐specific expression of a splice variant in the II‐III cytoplasmic loop of Cacna1b

“…However, we focus on CCK + INs because 100% of GABA release relies on Ca V 2.2 channels; therefore, the functional significance of e18a-Cacna1b has high potential [42]. Furthermore, this type of interneurons are linked to mood disorders [47,48], express relatively high levels of the cannabinoid receptor protein (CB1R) [49], and contribute to the behavioral tolerance of tetrahydrocannabinol [50]. Given that CB1R agonists downregulate Ca V 2.2 channels to inhibit GABA release in CCK + INs, our findings suggest an anatomical link between e18a splicing in Cacna1b and the effects of CB1R agonists of transmitter release.…”

Tissue and cell-type specific expression of a splice variant in the II-III cytoplasmic loop ofCacna1b

“…Taken together our results strongly suggest that +e18a-Cacna1b pre-mRNA is expressed at higher levels in CCK + INs relative to CaMKIIa + PNs. CCK + INs are linked to mood disorders [46,47], express relatively high levels of the cannabinoid receptor protein (CB1R) [48], and contribute to the behavioral tolerance of tetrahydrocannabinol [49]. Given that CB1R agonists downregulate CaV2.2 channels to inhibit GABA release in CCK + INs, our findings suggest an anatomical link between e18a splicing in Cacna1b and the effects of CB1R agonists of transmitter release.…”

Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression

“…Still, the downregulation of p11 in cultured cells increased the localization of Kv3.1 to the cell membrane but reduced it from the Golgi, supporting the idea that p11 regulates the internalization of the channel from the cell membrane. p11 is essential for the trafficking of diverse ion channels, including: TASK1, ASIC1a, NaV1.8, as well as that of metabotropic G-protein coupled receptors 11,16,23,25,30,31 . It was suggested that association of p11 with ion channels masks their endoplasmic reticulum retention signal 22 .…”

“…This is in line with previous reports showing that deficits in reward and motivation-related behaviors are found in mice with constitutive deletion of p11 or in those with conditional deletion in the cholinergic neurons of the nucleus accumbens 11,35,36 . The idea that differences in mood-related behaviors are regulated by p11 in different cell types and brain regions is supported by the fact that the behavioral response to SSRIs is impaired in mice with deletion of p11 from hippocampal CCK, mossy cells and layer 5a cortical cells, but not cholinergic accumbal cells 16,32,35,37 . Taken together, the current study identifies a unique role for p11 in DG PV cells in mediating anxiolytic response and resilience for depression, as well as in regulating the behavioral response to chronic antidepressant treatment.…”

“…In CCK cells, p11 regulates the surface levels of the 5-HT1B serotonergic receptor to initiate the response to antidepressants, an effect mediated by disinhibition of PV cells 16 . Still, the mechanism by which p11 directly regulates the function of PV cells remains unknown.…”