The role of hippocampal mossy cells in antidepressant actions

Abstract

Most antidepressants, including selective serotonin reuptake inhibitors (SSRIs), initiate their drug actions by rapid elevation of serotonin, but they take several weeks to achieve ther-apeutic onset. This therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment. Mossy cells are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function. Here I show that neuronal activity of hippocampal mossy cells is enhanced by chronic, but not acute, SSRI administration. Behavioral and neurogenic effects of chronic treatment with the SSRI, fluoxetine, are abolished by mossy cell-specific knockout of p11 or Smarca3 or by an inhibi-tion of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Fur-thermore, simple chemogenetic activation of mossy cells using Gq-DREADD is sufficient to elevate the proliferation and survival of the neural stem cells. Conversely, acute chemogenetic inhibition of mossy cells using Gi-DREADD impairs behavioral and neurogenic responses to chronic administration of SSRI. In addition, modulations of mossy cell activity are influence to excitation-inhibition balance in dentate gyrus. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. These results indicate that compounds that target mossy cell activity would be attractive candidates for the development of newer antidepressant medications.