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Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment

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 therapeutic 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 we 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 inhibition of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Furthermore, 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. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. Our results indicate that compounds that target mossy cell activity would be attractive candidates for the development of new antidepressant medications.

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Acknowledgements

We are grateful to Dr. Helen Scharfman (New York University, USA) for helpful advice and discussion and also to Dr. Kazu Nakazawa (University of Alabama, USA) for kindly sharing [Calcrl]-Cre transgenic mice. This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT (NRF-2017M3C7A1048448 to YSO); the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03935615 to YSO); the Bio & Medical Technology Development Program (NRF-2017M3A9G8084463 to YSO); the DGIST R&D Program of the Ministry of Science, ICT and Future Planning (18-BD-0402 to YSO); KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (18-BR-04-03 to YSO); 2014 NARSAD YI AWARD (Grant No. 20695 to YSO). In addition, this work was supported by the United States Army Medical Research and Material Command (USAMRMC) under Award No.W81XWH-16-1-0681 (to PG), funds received from The JPB Foundation, Award No. 475 (to PG) and funds received from the Black Family Foundation (to PG).

Author information

SO, JC, PG, and YSO designed the experiments. SO and JA performed and analyzed the behavior test. JC performed and analyzed electrophysiology experiments. SO performed and analyzed immunofluorescence data. SO, JC, PG, and YSO wrote the paper.

Correspondence to Yong-Seok Oh.

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