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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13–25.
Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006;7:137–51.
Holtzheimer PE, Mayberg HS. Stuck in a rut: rethinking depression and its treatment. Trends Neurosci. 2011;34:1–9.
Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010;167:1305–20.
Covington HE 3rd, Vialou V, Nestler EJ. From synapse to nucleus: novel targets for treating depression. Neuropharmacology. 2010;58:683–93.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiat. 2006;163:1905–17.
Amaral DG. A Golgi study of cell types in the hilar region of the hippocampus in the rat. J Comp Neurol. 1978;182:851–914.
Scharfman HE. Electrophysiological evidence that dentate hilar mossy cells are excitatory and innervate both granule cells and interneurons. J Neurophysiol. 1995;74:179–94.
Blasco-Ibanez JM, Freund TF. Distribution, ultrastructure, and connectivity of calretinin-immunoreactive mossy cells of the mouse dentate gyrus. Hippocampus. 1997;7:307–20.
Henze DA, Buzsaki G. Hilar mossy cells: functional identification and activity in vivo. Prog Brain Res. 2007;163:199–216.
Scharfman HE. The enigmatic mossy cell of the dentate gyrus. Nat Rev Neurosci. 2016;17:562–75.
Jinde S, Zsiros V, Nakazawa K. Hilar mossy cell circuitry controlling dentate granule cell excitability. Front Neural Circuits. 2013;7:14.
Sun Y, Grieco SF, Holmes TC, Xu X. Local and long-range circuit connections to hilar mossy cells in the dentate gyrus. eNeuro. 2017;4. https://doi.org/10.1523/ENEURO.0097-17.2017.
Gage FH, Thompson RG. Differential distribution of norepinephrine and serotonin along the dorsal-ventral axis of the hippocampal formation. Brain Res Bull. 1980;5:771–3.
Lisman JE, Grace AA. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron. 2005;46:703–13.
Patel A, Bulloch K. Type II glucocorticoid receptor immunoreactivity in the mossy cells of the rat and the mouse hippocampus. Hippocampus. 2003;13:59–66.
Danielson NB, Turi GF, Ladow M, Chavlis S, Petrantonakis PC, Poirazi P, et al. In vivo imaging of dentate gyrus mossy cells in behaving mice. Neuron. 2017;93:552–59.
GoodSmith D, Chen X, Wang C, Kim SH, Song H, Burgalossi A, et al. Spatial representations of granule cells and mossy cells of the dentate gyrus. Neuron. 2017;93:677–90.
Senzai Y, Buzsaki G. Physiological properties and behavioral correlates of hippocampal granule cells and mossy cells. Neuron. 2017;93:691–704.
Nakazawa K. Dentate mossy cell and pattern separation. Neuron. 2017;93:465–7.
Jinde S, Zsiros V, Jiang Z, Nakao K, Pickel J, Kohno K, et al. Hilar mossy cell degeneration causes transient dentate granule cell hyperexcitability and impaired pattern separation. Neuron. 2012;76:1189–200.
Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80.
Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P. p11 and its role in depression and therapeutic responses to antidepressants. Nat Rev Neurosci. 2013;14:673–80.
Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Lievano M, Ghose S, et al. Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med. 2010;2:54ra76.
Anisman H, Du L, Palkovits M, Faludi G, Kovacs GG, Szontagh-Kishazi P, et al. Serotonin receptor subtype and p11 mRNA expression in stress-relevant brain regions of suicide and control subjects. J Psychiatry Neurosci. 2008;33:131–41.
Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Lievano M, Ghose S, et al. Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med. 2010;2:54ra76.
Egeland M, Warner-Schmidt J, Greengard P, Svenningsson P. Neurogenic effects of fluoxetine are attenuated inp11 (S100A10) knockout mice. Biol Psychiatry. 2010;67:1048–56.
Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P, et al. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry. 2010;68:528–35.
Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N. Identification of the cortical neurons that mediate antidepressant responses. Cell. 2012;149:1152–63.
Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA. 2012;109:11360–5.
Eriksson TM, Alvarsson A, Stan TL, Zhang X, Hascup KN, Hascup ER, et al. Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampalp11. Mol Psychiatry. 2013;18:1096–105.
Oh YS, Gao P, Lee KW, Ceglia I, Seo JS, Zhang X, et al. SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell. 2013;152:831–43.
Lee KW, Westin L, Kim J, Chang JC, Oh YS, Amreen B, et al. Alteration by p11 of mGluR5 localization regulates depression-like behaviors. Mol Psychiatry. 2015;20:1546–56.
Milosevic A, Liebmann T, Knudsen M, Schintu N, Svenningsson P, Greengard P. Cell- and region-specific expression of depression-related proteinp11 (S100a10) in the brain. J Comp Neurol. 2017;525:955–75.
Seo JS, Zhong P, Liu A, Yan Z, Greengard P. Elevation of p11 in lateral habenula mediates depression-like behavior. Mol Psychiatry 2017;23:1113.
Gerke V, Creutz CE, Moss SE. Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol. 2005;6:449–61.
Medrihan L, Sagi Y, Inde Z, Krupa O, Daniels C, Peyrache A, et al. Initiation of behavioral response to antidepressants by cholecystokinin neurons of the dentate gyrus. Neuron 2017;95:564–76.
Gangarossa G, Longueville S, De Bundel D, Perroy J, Herve D, Girault JA, et al. Characterization of dopamine D1 and D2 receptor-expressing neurons in the mouse hippocampus. Hippocampus. 2012;22:2199–207.
Puighermanal E, Biever A, Espallergues J, Gangarossa G, De Bundel D, Valjent E. drd2-cre:ribotag mouse line unravels the possible diversity of dopamine d2 receptor-expressing cells of the dorsal mouse hippocampus. Hippocampus. 2015;25:858–75.
Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur Neuropsychopharmacol. 2010;20:1–17.
Duman RS, Malberg J, Nakagawa S, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry. 2000;48:732–9.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9.
Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, et al. Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci. 2005;21:1–14.
Scharfman HE, Myers CE. Hilar mossy cells of the dentate gyrus: a historical perspective. Front Neural Circuits. 2012;6:106.
Moretto JN, Duffy AM, Scharfman HE. Acute restraint stress decreases c-fos immunoreactivity in hilar mossy cells of the adult dentate gyrus. Brain Struct Funct. 2017;222:2405–19.
Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology. 2005;52:90–110.
Dragunow M, Robertson HA. Kindling stimulation induces c-fos protein(s) in granule cells of the rat dentate gyrus. Nature. 1987;329:441–2.
Das S, Shetty P, Valapala M, Dasgupta S, Gryczynski Z, Vishwanatha JK. Signal transducer and activator of transcription 6 (STAT6) is a novel interactor of annexin A2 in prostate cancer cells. Biochemistry. 2010;49:2216–26.
Liu J, Vishwanatha JK. Regulation of nucleo-cytoplasmic shuttling of human annexin A2: a proposed mechanism. Mol Cell Biochem. 2007;303:211–20.
Wang JW, David DJ, Monckton JE, Battaglia F, Hen R. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci. 2008;28:1374–84.
David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93.
Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Agustsdottir A, et al. Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science. 2011;334:1731–4.
Castrén E. Is mood chemistry? Nat Rev Neurosci. 2005;6:241.
Shuto T, Kuroiwa M, Sotogaku N, Kawahara Y, Oh Y-S, Jang J-H, et al. Obligatory roles of dopamine D1 receptors in the dentate gyrus in antidepressant actions of a selective serotonin reuptake inhibitor, fluoxetine. Mol Psychiatry. 2018 https://doi.org/10.1038/s41380-018-0316-x. [EPub ahead of print].
Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894–902.
Scharfman HE, Schwartzkroin PA. Electrophysiology of morphologically identified mossy cells of the dentate hilus recorded in guinea pig hippocampal slices. J Neurosci. 1988;8:3812–21.
Bui AD, Nguyen TM, Limouse C, Kim HK, Szabo GG, Felong S, et al. Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory. Science. 2018;359:787–90.
Chancey JH, Poulsen DJ, Wadiche JI, Overstreet-Wadiche L. Hilar mossy cells provide the first glutamatergic synapses to adult-born dentate granule cells. J Neurosci. 2014;34:2349–54.
Imoto Y, Kira T, Sukeno M, Nishitani N, Nagayasu K, Nakagawa T, et al. Role of the 5-HT4 receptor in chronic fluoxetine treatment-induced neurogenic activity and granule cell dematuration in the dentate gyrus. Mol Brain. 2015;8:29.
Samuels BA, Anacker C, Hu A, Levinstein MR, Pickenhagen A, Tsetsenis T, et al. 5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response. Nat Neurosci. 2015;18:1606–16.
Segi-Nishida E. The effect of serotonin-targeting antidepressants on neurogenesis and neuronal maturation of the hippocampus mediated via 5-HT1A and 5-HT4 receptors. Front Cell Neurosci. 2017;11:142.
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-2017M3A9G8084463Â 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
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Oh, SJ., Cheng, J., Jang, JH. et al. Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment. Mol Psychiatry 25, 1215–1228 (2020). https://doi.org/10.1038/s41380-019-0384-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-019-0384-6
This article is cited by
-
Prediction of early improvement of major depressive disorder to antidepressant medication in adolescents with radiomics analysis after ComBat harmonization based on multiscale structural MRI
BMC Psychiatry (2023)
-
Reduction of p11 in dorsal raphe nucleus serotonergic neurons mediates depression-like behaviors
Translational Psychiatry (2023)
-
Mesenchymal stromal cells alleviate depressive and anxiety-like behaviors via a lung vagal-to-brain axis in male mice
Nature Communications (2023)
-
LD block disorder-specific pleiotropic roles of novel CRHR1 in type 2 diabetes and depression disorder comorbidity
European Archives of Psychiatry and Clinical Neuroscience (2023)
-
Update on GPCR-based targets for the development of novel antidepressants
Molecular Psychiatry (2022)