Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility

Molecular Psychiatry volume 29, pages 2967–2978 (2024)Cite this article

Subjects

A Correction to this article was published on 01 July 2024

This article has been updated

Abstract

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute cellular stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. At the mechanistic levels, the microglial secretion of High-Mobility Group Box (HMGB), which is known to bind with and regulate the NMDA-type glutamate receptors, was elevated. Consequently, the hyperactivation of the prelimbic layer 5 excitatory neurons, a neural substrate for cognitive inflexibility, was also observed. The upregulation of the microglial HMGB signaling and neuronal hyperactivation were normalized by the pharmacological and microglia-specific genetic interventions. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The N-GAPDH cascade underlies stress-induced cognitive inflexibility in LSM mouse model.
Fig. 2: The N-GAPDH cascade is selectively upregulated in microglia of LSM mouse model.
Fig. 3: Microglia-specific genetic intervention to the N-GAPDH cascade prevents behavioral deficits in the rule-shifting paradigm in LSM mouse model.
Fig. 4: Both pharmacological and microglia-specific genetic intervention to the N-GAPDH cascade normalize hyperactivation of the prelimbic layer 5 excitatory neurons in LSM mouse model.
Fig. 5: N-GAPDH cascade-mediated HMGB1 upregulation in microglia in LSM mouse model; an antibody against HMGB1 normalizes hyperactivation of the prelimbic layer 5 excitatory neurons in LSM mouse model.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Change history

References

  1. Ionescu T. Exploring the nature of cognitive flexibility. N Ideas Psychol. 2012;30:190–200.

    Article  Google Scholar 

  2. Spellman T, Svei M, Kaminsky J, Manzano-Nieves G, Liston C. Prefrontal deep projection neurons enable cognitive flexibility via persistent feedback monitoring. Cell. 2021;184:2750–66.e17.

    Article  CAS  PubMed  Google Scholar 

  3. Cho KK, Hoch R, Lee AT, Patel T, Rubenstein JL, Sohal VS. Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice. Neuron. 2015;85:1332–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stokes MG, Buschman TJ, Miller EK. The Wiley Handbook of Cognitive Control. Hoboken: Wiley-Blackwell; 2017.

  5. Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10:410–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Diamond A. Executive functions. Annu Rev Psychol. 2013; 64:135–68.

    Article  PubMed  Google Scholar 

  7. Plessow F, Fischer R, Kirschbaum C, Goschke T. Inflexibly focused under stress: acute psychosocial stress increases shielding of action goals at the expense of reduced cognitive flexibility with increasing time lag to the stressor. J Cogn Neurosci. 2011;23:3218–27.

    Article  PubMed  Google Scholar 

  8. Baudic S, Barba GD, Thibaudet MC, Smagghe A, Remy P, Traykov L. Executive function deficits in early Alzheimer’s disease and their relations with episodic memory. Arch Clin Neuropsychol. 2006;21:15–21.

    Article  PubMed  Google Scholar 

  9. Floresco SB, Zhang Y, Enomoto T. Neural circuits subserving behavioral flexibility and their relevance to schizophrenia. Behav Brain Res. 2009;204:396–409.

    Article  PubMed  Google Scholar 

  10. Gruber AJ, Calhoon GG, Shusterman I, Schoenbaum G, Roesch MR, O’Donnell P. More is less: a disinhibited prefrontal cortex impairs cognitive flexibility. J Neurosci. 2010;30:17102–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Malloy P, McLaughlin NCR. Neuropsychology of Everyday Functioning. New York: Guilford Publications; 2010.

  12. Marshall GA, Rentz DM, Frey MT, Locascio JJ, Johnson KA, Sperling RA, et al. Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer’s disease. Alzheimers Dement. 2011;7:300–8.

    Article  PubMed  Google Scholar 

  13. Coughlin JM, Yang K, Marsman A, Pradhan S, Wang M, Ward RE, et al. A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia. Mol Psychiatry. 2021;26:3502–11.

    Article  CAS  PubMed  Google Scholar 

  14. Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020; 9:42.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang AM, Pradhan S, Coughlin JM, Trivedi A, DuBois SL, Crawford JL, et al. Assessing brain metabolism with 7-T proton magnetic resonance spectroscopy in patients with first-episode psychosis. JAMA Psychiatry. 2019;76:314–23.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Coughlin JM, Ishizuka K, Kano SI, Edwards JA, Seifuddin FT, Shimano MA, et al. Marked reduction of soluble superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with recent-onset schizophrenia. Mol Psychiatry. 2013;18:10–1.

    Article  CAS  PubMed  Google Scholar 

  17. Coughlin JM, Hayes LN, Tanaka T, Xiao M, Yolken RH, Worley P, et al. Reduced superoxide dismutase-1 (SOD1) in cerebrospinal fluid of patients with early psychosis in association with clinical features. Schizophr Res. 2017;183:64–9.

    Article  PubMed  Google Scholar 

  18. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hammond TR, Marsh SE, Stevens B. Immune signaling in neurodegeneration. Immunity. 2019;50:955–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hayes LN, Severance EG, Leek JT, Gressitt KL, Rohleder C, Coughlin JM, et al. Inflammatory molecular signature associated with infectious agents in psychosis. Schizophr Bull. 2014;40:963–72.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tanaka T, Matsuda T, Hayes LN, Yang S, Rodriguez K, Severance EG, et al. Infection and inflammation in schizophrenia and bipolar disorder. Neurosci Res. 2017;115:59–63.

    Article  CAS  PubMed  Google Scholar 

  22. Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science. 2016;353:777–83.

    Article  CAS  PubMed  Google Scholar 

  23. Rolstad S, Jakobsson J, Sellgren C, Isgren A, Ekman CJ, Bjerke M, et al. CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment. Eur Neuropsychopharmacol. 2015;25:1091–8.

    Article  CAS  PubMed  Google Scholar 

  24. Janelidze S, Mattsson N, Stomrud E, Lindberg O, Palmqvist S, Zetterberg H, et al. CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurology. 2018;91:e867–e77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Clark AL, Weigand AJ, Thomas KR, Solders SK, Delano-Wood L, Bondi MW, et al. Elevated inflammatory markers and arterial stiffening exacerbate tau but not amyloid pathology in older adults with mild cognitive impairment. J Alzheimers Dis. 2021;80:1451–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dawson TM, Golde TE, Lagier-Tourenne C. Animal models of neurodegenerative diseases. Nat Neurosci. 2018;21:1370–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gotz J, Bodea LG, Goedert M. Rodent models for Alzheimer disease. Nat Rev Neurosci. 2018;19:583–98.

    Article  CAS  PubMed  Google Scholar 

  28. Landek-Salgado MA, Faust TE, Sawa A. Molecular substrates of schizophrenia: homeostatic signaling to connectivity. Mol Psychiatry. 2016;21:10–28.

    Article  CAS  PubMed  Google Scholar 

  29. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J. Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun. 2008;22:469–86.

    Article  CAS  PubMed  Google Scholar 

  30. Bavley CC, Kabir ZD, Walsh AP, Kosovsky M, Hackett J, Sun H, et al. Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress. Mol Psychiatry. 2021;26:2286–98.

    Article  CAS  PubMed  Google Scholar 

  31. Chen S, Zhang H, Pu H, Wang G, Li W, Leak RK, et al. n-3 PUFA supplementation benefits microglial responses to myelin pathology. Sci Rep. 2014;4:7458.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kroener S, Mulholland PJ, New NN, Gass JT, Becker HC, Chandler LJ. Chronic alcohol exposure alters behavioral and synaptic plasticity of the rodent prefrontal cortex. PLoS One. 2012;7:e37541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shin Yim Y, Park A, Berrios J, Lafourcade M, Pascual LM, Soares N, et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature. 2017;549:482–7.

    Article  PubMed  Google Scholar 

  34. Tezuka T, Tamura M, Kondo MA, Sakaue M, Okada K, Takemoto K, et al. Cuprizone short-term exposure: astrocytic IL-6 activation and behavioral changes relevant to psychosis. Neurobiol Dis. 2013;59:63–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep. 2019;9:5790.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Beier EE, Neal M, Alam G, Edler M, Wu LJ, Richardson JR. Alternative microglial activation is associated with cessation of progressive dopamine neuron loss in mice systemically administered lipopolysaccharide. Neurobiol Dis. 2017;108:115–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, et al. Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci. 2012;32:11706–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018;556:332–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Norden DM, Trojanowski PJ, Villanueva E, Navarro E, Godbout JP. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia. 2016;64:300–16.

    Article  PubMed  Google Scholar 

  40. He Y, Wang Y, Yu H, Tian Y, Chen X, Chen C, et al. Protective effect of Nr4a2 (Nurr1) against LPS-induced depressive-like behaviors via regulating activity of microglia and CamkII neurons in anterior cingulate cortex. Pharm Res. 2023;191:106717.

    Article  CAS  Google Scholar 

  41. Tian Y, Chen X, Wang Y, He Y, Chen C, Yu H, et al. Neuroinflammatory transcriptional signatures in the entorhinal cortex based on lipopolysaccharide-induced depression model in mice. Biochem Biophys Res Commun. 2022;590:109–16.

    Article  CAS  PubMed  Google Scholar 

  42. Siemsen BM, Landin JD, McFaddin JA, Hooker KN, Chandler LJ, Scofield MD. Chronic intermittent ethanol and lipopolysaccharide exposure differentially alter Iba1-derived microglia morphology in the prelimbic cortex and nucleus accumbens core of male Long-Evans rats. J Neurosci Res. 2021;99:1922–39.

    Article  CAS  PubMed  Google Scholar 

  43. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shahani N, Sawa A. Nitric oxide signaling and nitrosative stress in neurons: role for S-nitrosylation. Antioxid Redox Signal. 2011;14:1493–504.

    Article  CAS  PubMed  Google Scholar 

  45. Tristan C, Shahani N, Sedlak TW, Sawa A. The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal. 2011;23:317–23.

    Article  CAS  PubMed  Google Scholar 

  46. Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, Cordelieres FP, et al. Vesicular glycolysis provides on-board energy for fast axonal transport. Cell. 2013;152:479–91.

    Article  CAS  PubMed  Google Scholar 

  47. Seidler NW. GAPDH and intermediary metabolism. Adv Exp Med Biol. 2013;985:37–59.

    Article  PubMed  Google Scholar 

  48. Chang CH, Curtis JD, Maggi LB Jr., Faubert B, Villarino AV, O’Sullivan D, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013;153:1239–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol. 2005;7:665–74.

    Article  CAS  PubMed  Google Scholar 

  50. Sawa A, Khan AA, Hester LD, Snyder SH. Glyceraldehyde-3-phosphate dehydrogenase: nuclear translocation participates in neuronal and nonneuronal cell death. Proc Natl Acad Sci USA. 1997;94:11669–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, et al. Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci USA. 2006;103:3887–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang M, Kariya T, Genri N, Sasaki H, Sasaki M, Ramos A, et al. Nuclear GAPDH cascade mediates pathological cardiac hypertrophy. bioRxiv. 2024; https://doi.org/10.1101/844902.

  53. Guha P, Harraz MM, Snyder SH. Cocaine elicits autophagic cytotoxicity via a nitric oxide-GAPDH signaling cascade. Proc Natl Acad Sci USA. 2016;113:1417–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Johnson AW, Jaaro-Peled H, Shahani N, Sedlak TW, Zoubovsky S, Burruss D, et al. Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness. Proc Natl Acad Sci USA. 2013;110:12462–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Moore H, Geyer MA, Carter CS, Barch DM. Harnessing cognitive neuroscience to develop new treatments for improving cognition in schizophrenia: CNTRICS selected cognitive paradigms for animal models. Neurosci Biobehav Rev. 2013;37:2087–91.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Sen N, Hara MR, Kornberg MD, Cascio MB, Bae BI, Shahani N, et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol. 2008;10:866–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sahasrabuddhe V, Ghosh HS. Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain. Cell Rep. 2022;38:110252.

    Article  CAS  PubMed  Google Scholar 

  58. McKinsey GL, Lizama CO, Keown-Lang AE, Niu A, Santander N, Larpthaveesarp A, et al. A new genetic strategy for targeting microglia in development and disease. Elife. 2020;9:e54590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S, et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci. 2019;22:1021–35.

    Article  PubMed  Google Scholar 

  60. Heisler JM, Morales J, Donegan JJ, Jett JD, Redus L, O’Connor JC. The attentional set shifting task: a measure of cognitive flexibility in mice. J Vis Exp. 2015;96:51944.

  61. Feng S, Zou L, Wang H, He R, Liu K, Zhu H. RhoA/ROCK-2 pathway inhibition and tight junction protein upregulation by catalpol suppresses lipopolysaccaride-induced disruption of blood-brain barrier permeability. Molecules. 2018;23:2371.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Agarwal A, Wu PH, Hughes EG, Fukaya M, Tischfield MA, Langseth AJ, et al. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron. 2017;93:587–605 e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhou P, Resendez SL, Rodriguez-Romaguera J, Jimenez JC, Neufeld SQ, Giovannucci A, et al. Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data. Elife. 2018;7:e28728.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Pnevmatikakis EA, Soudry D, Gao Y, Machado TA, Merel J, Pfau D, et al. Simultaneous denoising, deconvolution, and demixing of calcium imaging data. Neuron. 2016;89:285–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Murugan M, Jang HJ, Park M, Miller EM, Cox J, Taliaferro JP, et al. Combined social and spatial coding in a descending projection from the prefrontal cortex. Cell. 2017;171:1663–77.e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol. 2016;37:608–20.

    Article  CAS  PubMed  Google Scholar 

  67. Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sochocka M, Diniz BS, Leszek J. Inflammatory response in the CNS: friend or foe? Mol Neurobiol. 2017;54:8071–89.

    Article  CAS  PubMed  Google Scholar 

  69. Enomoto T, Tse MT, Floresco SB. Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia. Biol Psychiatry. 2011;69:432–41.

    Article  CAS  PubMed  Google Scholar 

  70. Paine TA, Slipp LE, Carlezon WA Jr. Schizophrenia-like attentional deficits following blockade of prefrontal cortex GABAA receptors. Neuropsychopharmacology. 2011;36:1703–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lee S, Nam Y, Koo JY, Lim D, Park J, Ock J, et al. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat Chem Biol. 2014;10:1055–60.

    Article  CAS  PubMed  Google Scholar 

  72. Shi Y, Guo X, Zhang J, Zhou H, Sun B, Feng J. DNA binding protein HMGB1 secreted by activated microglia promotes the apoptosis of hippocampal neurons in diabetes complicated with OSA. Brain Behav Immun. 2018;73:482–92.

    Article  CAS  PubMed  Google Scholar 

  73. Fu L, Liu K, Wake H, Teshigawara K, Yoshino T, Takahashi H, et al. Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. Sci Rep. 2017;7:1179.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Nestor J, Arinuma Y, Huerta TS, Kowal C, Nasiri E, Kello N, et al. Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J Exp Med. 2018;215:2554–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Pedrazzi M, Averna M, Sparatore B, Patrone M, Salamino F, Marcoli M, et al. Potentiation of NMDA receptor-dependent cell responses by extracellular high mobility group box 1 protein. PLoS One. 2012;7:e44518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Colell A, Green DR, Ricci JE. Novel roles for GAPDH in cell death and carcinogenesis. Cell Death Differ. 2009;16:1573–81.

    Article  CAS  PubMed  Google Scholar 

  77. Xu R, Serritella AV, Sen T, Farook JM, Sedlak TW, Baraban J, et al. Behavioral effects of cocaine mediated by nitric oxide-GAPDH transcriptional signaling. Neuron. 2013;78:623–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nakajima H, Kubo T, Ihara H, Hikida T, Danjo T, Nakatsuji M, et al. Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) polymerase-1 activation during oxidative/nitrosative stress in stroke. J Biol Chem. 2015;290:14493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Boukouris AE, Zervopoulos SD, Michelakis ED. Metabolic enzymes moonlighting in the nucleus: metabolic regulation of gene transcription. Trends Biochem Sci. 2016;41:712–30.

    Article  CAS  PubMed  Google Scholar 

  80. Yu X, Li S. Non-metabolic functions of glycolytic enzymes in tumorigenesis. Oncogene. 2017;36:2629–36.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Hao Zhang and the Flow Cytometry Core at JHSPH for providing sorting and analysis services. We thank Dr. Masayuki Sasaki for technical support. We thank Yukiko Lema for figure and manuscript organization. We also appreciate Melissa Landek-Salgado and Richard Farrell for thoughtful comments and editions of this manuscript. This work was supported by the grants from the National Institute of Health (MH-094268 Silvio O. Conte center, MH-105660, MH-107730), as well as the grants from NARSAD, Stanley, S-R/RUSK (to AS). This work was also supported by the Subsidies for Current Expenditures to Private Institutions of Higher Education from the Promotion and Mutual Aid Corporation for Private Schools of Japan (to KI).

Author information

Author notes

  1. These authors contributed equally: Adriana Ramos, Koko Ishizuka, Arisa Hayashida, Ho Namkung.

Authors and Affiliations

  1. Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Adriana Ramos, Lindsay N. Hayes, Barbara S. Slusher, Atsushi Saito & Akira Sawa

  2. Departments of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Koko Ishizuka, Arisa Hayashida, Rupali Srivastava, Noah Elkins, Trexy Palen, Elisa Carloni, Tsuyoshi Tsujimura, Barbara S. Slusher, Minae Niwa & Akira Sawa

  3. International Collaborative Research Administration, Juntendo University, Tokyo, Japan

    Arisa Hayashida

  4. Departments of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ho Namkung & Akira Sawa

  5. Departments of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Manling Zhang, Taro Kariya, Barbara S. Slusher & Eiki Takimoto

  6. Neurocircuitry of Motivation Section, National Institute on Drug Abuse, Baltimore, MD, USA

    Coleman Calva & Satoshi Ikemoto

  7. Departments of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Rana Rais, Barbara S. Slusher & Akira Sawa

  8. Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Rana Rais & Barbara S. Slusher

  9. Nihon Pharmaceutical University, Saitama, Japan

    Toshiaki Saitoh

  10. Departments of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Akira Sawa

  11. Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    Akira Sawa

Authors
  1. Adriana Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koko Ishizuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arisa Hayashida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ho Namkung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lindsay N. Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rupali Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Taro Kariya
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Noah Elkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Trexy Palen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Elisa Carloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tsuyoshi Tsujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Coleman Calva
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Satoshi Ikemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rana Rais
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Barbara S. Slusher
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Minae Niwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Atsushi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Toshiaki Saitoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Eiki Takimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Akira Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AS (Sawa) conceived the general ideas for this study. AR, KI, and AS (Sawa) designed experiments. AR, KI, AH, HN, LNH, RS, MZ, TK, NE, TP, EC, TT, CC, RR, MN, and AS performed the experiments and data analysis with guidance from SI, BSS, TS, ET, and AS (Sawa). AR, KI, and AS (Sawa) drafted the manuscript. All authors contributed to the discussion of the results and have approved the final manuscript to be published.

Corresponding author

Correspondence to Akira Sawa.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: The article Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility, written by Akira Sawa was originally published online on the publisher’s internet portal on 14.04.2024 with Open Access under a Creative Commons Attribution (CC BY) license 4.0. With the author’s/authors’ decision to cancel Open Access the copyright of the article changed on 24.05.2024 to © The Author(s), under exclusive licence to Springer Nature Limited 2024 with all rights reserved.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ramos, A., Ishizuka, K., Hayashida, A. et al. Nuclear GAPDH in cortical microglia mediates cellular stress-induced cognitive inflexibility. Mol Psychiatry 29, 2967–2978 (2024). https://doi.org/10.1038/s41380-024-02553-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-024-02553-1

This article is cited by

Search

Advanced search

Quick links