SpringerLink
Log in

FAM19A5/TAFA5, a novel neurokine, plays a crucial role in depressive-like and spatial memory-related behaviors in mice

  • Article
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

FAM19A5/TAFA5 is a member of the family with sequence similarity 19 with unknown function in emotional and cognitive regulation. Here, we reported that FAM19A5 was highly expressed in the embryonic and postnatal mouse brain, especially in the hippocampus. Behaviorally, genetic deletion of Fam19a5 resulted in increased depressive-like behaviors and impaired hippocampus-dependent spatial memory. These behavioral alterations were associated with the decreased expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-D-aspartic acid receptors, as well as significantly reduced glutamate release and neuronal activity in the hippocampus. Subsequently, these changes led to the decreased density of dendritic spines. In recent years, the roles of chronic stress participating in the development of depression have become increasingly clear, but the mechanism remains to be elucidated. We found that the levels of FAM19A5 in plasma and hippocampus of chronic stress-treated mice were significantly decreased whereas overexpression of human FAM19A5 selectively in the hippocampus could attenuate chronic stress-induced depressive-like behaviors. Taken together, our results revealed for the first time that FAM19A5 plays a key role in the regulation of depression and spatial cognition in the hippocampus. Furthermore, our study provided a new mechanism for chronic stress-induced depression, and also provided a potential biomarker for the diagnosis and a new strategy for the treatment of depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Expression of FAM19A5 in the embryonic and postnatal mouse brain.
Fig. 2: Depressive-like behaviors and spatial memory impairment in Fam19a5−/− mice.
Fig. 3: Decreased FAM19A5 participated in the chronic stress-induced depression.
Fig. 4: Downregulation of AMPA receptors and NMDA receptors in the hippocampus of Fam19a5−/− mice.
Fig. 5: Reduction of dendritic spine density, neuronal activity and glutamate release in Fam19a5 deficiency mice.

Similar content being viewed by others

References

  1. Tom Tang Y, Emtage P, Funk WD, Hu T, Arterburn M, Park EE, et al. TAFA: a novel secreted family with conserved cysteine residues and restricted expression in the brain. Genomics. 2004;83:727–34.

    Article  CAS  PubMed  Google Scholar 

  2. Lei X, Liu L, Terrillion CE, Karuppagounder SS, Cisternas P, Lay M, et al. FAM19A1, a brain-enriched and metabolically responsive neurokine, regulates food intake patterns and mouse behaviors. FASEB J. 2019;33:14734–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang X, Shen C, Chen X, Wang J, Cui X, Wang Y, et al. Tafa-2 plays an essential role in neuronal survival and neurobiological function in mice. Acta biochimica et biophysica Sin. 2018;50:984–95.

    Article  CAS  Google Scholar 

  4. Paulsen SJ, Christensen MT, Vrang N, Larsen LK. The putative neuropeptide TAFA5 is expressed in the hypothalamic paraventricular nucleus and is regulated by dehydration. Brain Res. 2008;1199:1–9.

    Article  CAS  PubMed  Google Scholar 

  5. Shahapal A, Cho EB, Yong HJ, Jeong I, Kwak H, Lee JK, et al. FAM19A5 expression during embryogenesis and in the adult traumatic brain of FAM19A5-LacZ knock-in mice. Front Neurosci. 2019;13:917.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kashevarova AA, Belyaeva EO, Nikonov AM, Plotnikova OV, Skryabin NA, Nikitina TV, et al. Compound phenotype in a girl with r(22), concomitant microdeletion 22q13.32-q13.33 and mosaic monosomy 22. Mol Cytogenetics. 2018;11:26.

    Article  Google Scholar 

  7. Wang Y, Chen D, Zhang Y, Wang P, Zheng C, Zhang S, et al. Novel adipokine, FAM19A5, inhibits neointima formation after injury through sphingosine-1-phosphate receptor 2. Circulation. 2018;138:48–63.

    Article  CAS  PubMed  Google Scholar 

  8. Akahoshi N, Ishizaki Y, Yasuda H, Murashima YL, Shinba T, Goto K, et al. Frequent spontaneous seizures followed by spatial working memory/anxiety deficits in mice lacking sphingosine 1-phosphate receptor 2. Epilepsy Behav. 2011;22:659–65.

    Article  PubMed  Google Scholar 

  9. Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. MacQueen G, Frodl T. The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry. 2011;16:252–64.

    Article  CAS  PubMed  Google Scholar 

  11. Bird CM, Burgess N. The hippocampus and memory: insights from spatial processing. Nat Rev Neurosci. 2008;9:182–94.

    Article  CAS  PubMed  Google Scholar 

  12. Rottenberg J. Emotions in depression what do we really know. Annu Rev Clin Psychol. 2017;13:241–63.

    Article  PubMed  Google Scholar 

  13. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894–902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13–25.

    Article  CAS  PubMed  Google Scholar 

  15. Pena CJ, Bagot RC, Labonte B, Nestler EJ. Epigenetic signaling in psychiatric disorders. J Mol Biol. 2014;426:3389–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2015;20:32–47.

    Article  CAS  PubMed  Google Scholar 

  17. Park C, Rosenblat JD, Brietzke E, Pan Z, Lee Y, Cao B, et al. Stress, epigenetics and depression: a systematic review. Neurosci Biobehav Rev. 2019;102:139–52.

    Article  CAS  PubMed  Google Scholar 

  18. Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011;13:22–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Aston-Jones G, Cohen JD. An integrative theory of locus coeruleus-norepinephrine function adaptive gain and optimal performance. Annu Rev Neurosci. 2005;28:403–50.

    Article  CAS  PubMed  Google Scholar 

  20. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.

    Article  CAS  PubMed  Google Scholar 

  21. McIntyre C, Saville J, Fuller M. Collection of cerebrospinal fluid from murine lateral ventricles for biomarker determination in mucopolysaccharidosis type IIIA. J Neurosci Methods. 2019;324:108314.

    Article  CAS  PubMed  Google Scholar 

  22. Zheng C, Chen D, Zhang Y, Bai Y, Huang S, Zheng D, et al. FAM19A1 is a new ligand for GPR1 that modulates neural stem-cell proliferation and differentiation. FASEB J. 2018;32:5874–90.

    Article  CAS  Google Scholar 

  23. Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, Grigoriev I, et al. Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron. 2009;61:85–100.

    Article  CAS  PubMed  Google Scholar 

  24. Angelova PR, Kasymov V, Christie I, Sheikhbahaei S, Turovsky E, Marina N, et al. Functional oxygen sensitivity of astrocytes. J Neurosci. 2015;35:10460–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kasymov V, Larina O, Castaldo C, Marina N, Patrushev M, Kasparov S, et al. Differential sensitivity of brainstem versus cortical astrocytes to changes in pH reveals functional regional specialization of astroglia. J Neurosci. 2013;33:435–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim KS, Han PL. Optimization of chronic stress paradigms using anxiety- and depression-like behavioral parameters. J Neurosci Res. 2006;83:497–507.

    Article  CAS  PubMed  Google Scholar 

  27. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–22.

    Article  CAS  PubMed  Google Scholar 

  28. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

    Article  CAS  PubMed  Google Scholar 

  29. Young P, Qiu L, Wang D, Zhao S, Gross J, Feng G. Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice. Nat Neurosci. 2008;11:721–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. **ong R, Verstraelen P, Demeester J, Skirtach AG, Timmermans JP, De Smedt SC, et al. Selective labeling of individual neurons in dense cultured networks with nanoparticle-enhanced photoporation. Front Cell Neurosci. 2018;12:80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Li Y, Zhong W, Wang D, Feng Q, Liu Z, Zhou J, et al. Serotonin neurons in the dorsal raphe nucleus encode reward signals. Nat Commun. 2016;7:10503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marvin JS, Scholl B, Wilson DE, Podgorski K, Kazemipour A, Muller JA, et al. Stability, affinity, and chromatic variants of the glutamate sensor iGluSnFR. Nat Methods. 2018;15:936–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci. 2017;18:335–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Henn FA, Vollmayr B. Stress models of depression: forming genetically vulnerable strains. Neurosci Biobehav Rev. 2005;29:799–804.

    Article  PubMed  Google Scholar 

  35. Cearley CN, Wolfe JH. Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol Ther. 2006;13:528–37.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang X, Lan Y, Xu J, Quan F, Zhao E, Deng C, et al. CellMarker: a manually curated resource of cell markers in human and mouse. Nucleic Acids Res. 2019;47:D721–8.

    Article  CAS  PubMed  Google Scholar 

  37. Carvalho AF, Rocha DQ, McIntyre RS, Mesquita LM, Kohler CA, Hyphantis TN, et al. Adipokines as emerging depression biomarkers: a systematic review and meta-analysis. J Psychiatr Res. 2014;59:28–37.

    Article  PubMed  Google Scholar 

  38. Machado-Vieira R, Gold PW, Luckenbaugh DA, Ballard ED, Richards EM, Henter ID, et al. The role of adipokines in the rapid antidepressant effects of ketamine. Mol Psychiatry. 2017;22:127–33.

    Article  CAS  PubMed  Google Scholar 

  39. Hammen C. Stress and depression. Annu Rev Clin Psychol. 2005;1:293–319.

    Article  PubMed  Google Scholar 

  40. Wingenfeld K, Wolf OT. Stress, memory, and the hippocampus. Front Neurol Neurosci. 2014;34:109–20.

    Article  PubMed  Google Scholar 

  41. Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006;7:137–51.

    Article  CAS  PubMed  Google Scholar 

  42. Chaki S. Beyond ketamine: new approaches to the development of safer antidepressants. Curr Neuropharmacol. 2017;15:963–76.

    Article  Google Scholar 

  43. Leuner B, Gould E. Structural plasticity and hippocampal function. Annu Rev Psychol. 2010;61:111–40. C111-113.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16:472–86.

    Article  CAS  PubMed  Google Scholar 

  45. Li MX, Zheng HL, Luo Y, He JG, Wang W, Han J, et al. Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs. Mol Psychiatry. 2018;23:556–68.

    Article  CAS  PubMed  Google Scholar 

  46. Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci. 2015;38:279–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yuksel C, Ongur D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry. 2010;68:785–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kaiser RH, Andrews-Hanna JR, Wager TD, Pizzagalli DA. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry. 2015;72:603–11.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Bliss TV, Collingridge GL. A synaptic model of memory long-term potentiation in the hippocampus. Nature. 1993;361:31–39.

    Article  CAS  PubMed  Google Scholar 

  51. Kessels HW, Malinow R. Synaptic AMPA receptor plasticity and behavior. Neuron. 2009;61:340–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kwon HB, Sabatini BL. Glutamate induces de novo growth of functional spines in develo** cortex. Nature. 2011;474:100–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102:75–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (81970536, 81974169, 31770940, 61527815 and 81671085), Natural Science Foundation of Bei**g Municipality (7192097) and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320006). We are grateful to Professor Dalong Ma (Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology and Center for Human Disease Genomics, Peking University) for his omics strategies and valuable suggestions.

Author information

Author notes

  1. These authors contributed equally: Shiyang Huang, Can Zheng, Guoguang ** She, Qingqing Li, Zhongtian Liu & Ying Wang

  2. Department of Clinical Laboratory, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    Can Zheng

  3. Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University; Key Laboratory for Neuroscience, Ministry of Education and National Health Commission, Peking University, Bei**g, 100191, China

    Guoguang **e, Yun Wang & Guo-Gang **ng

  4. Center for Human Disease Genomics, Peking University, Bei**g, 100191, China

    **zhang Wang, ** Lv & Ying Wang

  5. Department of Cell Biology, School of Basic Medical Sciences, Peking University, Bei**g, 100191, China

    Yun Bai

  6. Drug Non-Clinical Evaluation and Research Center of Guangzhou General Pharmaceutical Research Institute, Guangzhou, Guangdong, 510240, China

    Dixin Chen

Authors
  1. Shiyang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Can Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guoguang **e
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhanming Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. **zhang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yun Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dixin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. ** Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Weiwei Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shao** She
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qingqing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Zhongtian Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Guo-Gang **ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YW (Ying Wang), GGX (Guo-Gang **ng), and SYH conceived the project, designed the experiments and wrote the manuscript. SYH, CZ, and GGX (Guoguang **e) performed most of the experiments. ZMS, DXC, YZ, WWL, SPS, QQL, and ZTL performed some experiments or analyzed the data. PZW provided help for the bioinformatics analysis. PL provided help for prepared polyclonal antibodies. YB provided a few important advices for the work. YW (Yun Wang) provided behavioral experimental facilities. All authors have discussed the results and contributed to the drafting of the manuscript.

Corresponding authors

Correspondence to Guo-Gang **ng or Ying Wang.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, S., Zheng, C., **e, G. et al. FAM19A5/TAFA5, a novel neurokine, plays a crucial role in depressive-like and spatial memory-related behaviors in mice. Mol Psychiatry 26, 2363–2379 (2021). https://doi.org/10.1038/s41380-020-0720-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-0720-x

  • Springer Nature Limited

Search

Navigation