Abstract
Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress—CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics.
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
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data and materials availability
The RNA-Seq data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE123027.
References
Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010;167:1305–20.
Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 2012;35:47–56.
Enache D, Pariante CM, Mondelli V. Markers of central inflammation in major depressive disorder: a systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav Immun. 2019;72:268–75.
Yirmiya R, Weidenfeld J, Pollak Y, Morag M, Morag A, Avitsur R, et al. Cytokines, “depression due to a general medical condition,” and antidepressant drugs. Adv Exp Med Biol. 1999;461:283–316.
Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009;24:27–53.
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.
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.
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34.
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–86.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57.
Kern S, Skoog I, Börjesson-Hanson A, Blennow K, Zetterberg H, Ostling S, et al. Lower CSF interleukin-6 predicts future depression in a population-based sample of older women followed for 17 years. Brain Behav Immun. 2013;32:153–8.
Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology. 2011;36:2452–9.
Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci USA. 2011;108:9262–7.
Chung HS, Kim H, Bae H. Phenelzine (monoamine oxidase inhibitor) increases production of nitric oxide and proinflammatory cytokines via the NF-kappaB pathway in lipopolysaccharide-activated microglia cells. Neurochem Res. 2012;37:2117–24.
Nettis MA, Lombardo G, Hastings C, Zajkowska Z, Mariani N, Nikkheslat N, et al. Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial. Neuropsychopharmacology. 2021;46:939–48.
Attwells S, Setiawan E, Rusjan PM, Xu C, Hutton C, Rafiei D, et al. Translocator protein distribution volume predicts reduction of symptoms during open-label trial of celecoxib in major depressive disorder. Biol Psychiatry. 2020;88:649–56.
Savitz JB, Teague TK, Misaki M, Macaluso M, Wurfel BE, Meyer M, et al. Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2x2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry. 2018;8:27.
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41.
Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, et al. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. 2016;21:71–79.
Arteaga-Henriquez G, Simon MS, Burger B, Weidinger E, Wijkhuijs A, Arolt V, et al. Low-grade inflammation as a predictor of antidepressant and anti-inflammatory therapy response in mdd patients: a systematic review of the literature in combination with an analysis of experimental data collected in the EU-MOODINFLAME Consortium. Front Psychiatry. 2019;10:458.
Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci. 2015;38:637–58.
Singhal G, Baune BT. Microglia: an interface between the loss of neuroplasticity and depression. Front Cell Neurosci. 2017;11:270.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17:497–511.
Clark SM, Pocivavsek A, Nicholson JD, Notarangelo FM, Langenberg P, McMahon RP, et al. Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals. J Psychiatry Neurosci. 2016;41:386–94.
Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–59.
Bayer TA, Buslei R, Havas L, Falkai P. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett. 1999;271:126–8.
Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, et al. Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2008;42:151–7.
Li H, Sagar AP, Keri S. Microglial markers in the frontal cortex are related to cognitive dysfunctions in major depressive disorder. J Affect Disord. 2018;241:305–10.
Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, et al. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study. Biol Psychiatry. 2018;83:61–9.
Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.
Hannestad J, DellaGioia N, Gallezot JD, Lim K, Nabulsi N, Esterlis I, et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [(1)(1)C]PBR28 PET study. Brain Behav Immun. 2013;33:131–8.
Bufalino C, Hepgul N, Aguglia E, Pariante CM. The role of immune genes in the association between depression and inflammation: a review of recent clinical studies. Brain Behav Immun. 2013;31:31–47.
Pantazatos SP, Huang YY, Rosoklija GB, Dwork AJ, Arango V, Mann JJ. Whole-transcriptome brain expression and exon-usage profiling in major depression and suicide: evidence for altered glial, endothelial and ATPase activity. Mol Psychiatry. 2017;22:760–73.
Mahajan GJ, Vallender EJ, Garrett MR, Challagundla L, Overholser JC, Jurjus G, et al. Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2018;82:177–86.
Tynan RJ, Weidenhofer J, Hinwood M, Cairns MJ, Day TA, Walker FR. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun. 2012;26:469–79.
Hellwig S, Brioschi S, Dieni S, Frings L, Masuch A, Blank T, et al. Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice. Brain Behav Immun. 2016;55:126–37.
Rimmerman N, Schottlender N, Reshef R, Dan-Goor N, Yirmiya R. The hippocampal transcriptomic signature of stress resilience in mice with microglial fractalkine receptor (CX3CR1) deficiency. Brain Behav Immun. 2017;61:184–96.
Milior G, Lecours C, Samson L, Bisht K, Poggini S, Pagani F, et al. Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress. Brain Behav Immun. 2015;55:114–25.
Ekdahl CT, Kokaia Z, Lindvall O. Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience. 2009;158:1021–9.
Reshef R, Kudryavitskaya E, Shani-Narkiss H, Isaacson B, Rimmerman N, Mizrahi A, et al. The role of microglia and their CX3CR1 signaling in adult neurogenesis in the olfactory bulb. Elife. 2017;6:e30809.
Sierra A, Beccari S, Diaz-Aparicio I, Encinas JM, Comeau S, Tremblay ME. Surveillance, phagocytosis, and inflammation: how never-resting microglia influence adult hippocampal neurogenesis. Neural Plast. 2014;2014:610343.
Miller BR, Hen R. The current state of the neurogenic theory of depression and anxiety. Curr Opin Neurobiol. 2015;30:51–58.
Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, et al. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry. 2011;16:1177–88.
Du Preez A, Eum J, Eiben I, Eiben P, Zunszain PA, Pariante CM, et al. Do different types of stress differentially alter behavioural and neurobiological outcomes associated with depression in rodent models? A systematic review. Front Neuroendocrinol. 2021;61:100896.
Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49.
Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, et al. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci. 2011;31:6277–88.
Hinwood M, Morandini J, Day TA, Walker FR. Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex. 2012;22:1442–54.
Frank MG, Baratta MV, Sprunger DB, Watkins LR, Maier SF. Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun. 2007;21:47–59.
Wang YL, Han QQ, Gong WQ, Pan DH, Wang LZ, Hu W, et al. Microglial activation mediates chronic mild stress-induced depressive- and anxiety-like behavior in adult rats. J Neuroinflammation. 2018;15:21.
Tong L, Gong Y, Wang P, Hu W, Wang J, Chen Z, et al. microglia loss contributes to the development of major depression induced by different types of chronic stresses. Neurochem Res. 2017;42:2698–711.
Cai Z, Ye T, Xu X, Gao M, Zhang Y, Wang D, et al. Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable stress. Prog Neuropsychopharmacol Biol Psychiatry. 2020;101:109931.
Kreisel T, Frank MG, Licht T, Reshef R, Ben-Menachem-Zidon O, Baratta MV, et al. Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry. 2014;19:699–709.
Gong Y, Tong L, Yang R, Hu W, Xu X, Wang W, et al. Dynamic changes in hippocampal microglia contribute to depressive-like behavior induced by early social isolation. Neuropharmacology. 2018;135:223–33.
Maes M, Song C, Yirmiya R. Targeting IL-1 in depression. Expert Opin Thera Targets. 2012;16:1097–112.
Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, et al. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry. 2008;13:717–28.
Bassett B, Subramaniyam S, Fan Y, Varney S, Pan H, Carneiro AMD, et al. Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis. Brain Behav Immun. 2021;91:519–30.
Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007;357:1939–45.
Goldfarb S, Fainstein N, Ben-Hur T. Electroconvulsive stimulation attenuates chronic neuroinflammation. JCI Insight. 2020;5:e137028.
Goldfarb S, Fainstein N, Ganz T, Vershkov D, Lachish M, Ben-Hur T. Electric neurostimulation regulates microglial activation via retinoic acid receptor alpha signaling. Brain Behav Immun. 2021;96:40–53.
Sepulveda-Rodriguez A, Li P, Khan T, Ma JD, Carlone CA, Bozzelli PL, et al. Electroconvulsive shock enhances responsive motility and purinergic currents in microglia in the mouse hippocampus. eNeuro. 2019;6:ENEURO.0056-19.2019.
Jinno S, Kosaka T. Reduction of Iba1-expressing microglial process density in the hippocampus following electroconvulsive shock. Exp Neurol. 2008;212:440–7.
van Buel EM, Sigrist H, Seifritz E, Fikse L, Bosker FJ, Schoevers RA, et al. Mouse repeated electroconvulsive seizure (ECS) does not reverse social stress effects but does induce behavioral and hippocampal changes relevant to electroconvulsive therapy (ECT) side-effects in the treatment of depression. PLoS One. 2017;12:e0184603.
Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15:300–12.
Mondelli V, Vernon AC, Turkheimer F, Dazzan P, Pariante CM. Brain microglia in psychiatric disorders. Lancet Psychiatry. 2017;4:563–72.
Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation. 2015;12:139.
Jansson L, Wennstrom M, Johanson A, Tingstrom A. Glial cell activation in response to electroconvulsive seizures. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1119–28.
Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21:2580–8.
Reis DJ, Casteen EJ, Ilardi SS. The antidepressant impact of minocycline in rodents: a systematic review and meta-analysis. Sci Rep. 2019;9:261.
Rosenblat JD, McIntyre RS. Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials. J Affect Disord. 2018;227:219–25.
Han Y, Zhang L, Wang Q, Zhang D, Zhao Q, Zhang J, et al. Minocycline inhibits microglial activation and alleviates depressive-like behaviors in male adolescent mice subjected to maternal separation. Psychoneuroendocrinology. 2019;107:37–45.
Rotheneichner P, Lange S, O’Sullivan A, Marschallinger J, Zaunmair P, Geretsegger C, et al. Hippocampal neurogenesis and antidepressive therapy: shocking relations. Neural Plast. 2014;2014:723915.
Brooks AK, Lawson MA, Smith RA, Janda TM, Kelley KW, McCusker RH. Interactions between inflammatory mediators and corticosteroids regulate transcription of genes within the Kynurenine Pathway in the mouse hippocampus. J Neuroinflamm. 2016;13:16.
Miller CL, Llenos IC, Dulay JR, Weis S. Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res. 2006;1073:25–37.
Ogura Y, Parsons WH, Kamat SS, Cravatt BF. A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines. Nat Chem Biol. 2016;12:669.
Haslinger A, Schwarz TJ, Covic M, Lie DC. Expression of Sox11 in adult neurogenic niches suggests a stage-specific role in adult neurogenesis. Eur J Neurosci. 2009;29:2103–14.
Takamura N, Nakagawa S, Masuda T, Boku S, Kato A, Song N, et al. The effect of dopamine on adult hippocampal neurogenesis. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;50:116–24.
Rossato JI, Bevilaqua LRM, Izquierdo I, Medina JH, Cammarota M. Dopamine Controls Persistence of Long-Term Memory Storage. Science. 2009;325:1017–20.
Kreisel T, Wolf B, Keshet E, Licht T. Unique role for dentate gyrus microglia in neuroblast survival and in VEGF-induced activation. Glia. 2019;67:594–618.
Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16:1896–905.
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–47.
Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N, Sola PR, et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci. 2017;20:1162.
Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol. 2003;33:970–9.
Goldberg MV, Drake CG. LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol. 2011;344:269–78.
Deczkowska A, Amit I, Schwartz M. Microglial immune checkpoint mechanisms. Nat Neurosci. 2018;21:779–86.
Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013;155:1596–609.
Reshef R, Kreisel T, Beroukhim Kay D, Yirmiya R. Microglia and their CX3CR1 signaling are involved in hippocampal- but not olfactory bulb-related memory and neurogenesis. Brain Behav Immun. 2014;41:239–50.
Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9:268–75.
Sierra A, Tremblay ME, Wake H. Never-resting microglia: physiological roles in the healthy brain and pathological implications. Front Cell Neurosci. 2014;8:240.
Rice RA, Spangenberg EE, Yamate-Morgan H, Lee RJ, Arora RP, Hernandez MX, et al. Elimination of microglia improves functional outcomes following extensive neuronal loss in the hippocampus. J Neurosci. 2015;35:9977–89.
Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82:380–97.
Walter TJ, Crews FT. Microglial depletion alters the brain neuroimmune response to acute binge ethanol withdrawal. J Neuroinflammation. 2017;14:86.
Yang X, Ren H, Wood K, Li M, Qiu S, Shi FD, et al. Depletion of microglia augments the dopaminergic neurotoxicity of MPTP. FASEB J. 2018;32:3336–45.
Wahlund B, Piazza P, von Rosen D, Liberg B, Liljenström H. Seizure (Ictal)-EEG characteristics in subgroups of depressive disorder in patients receiving electroconvulsive therapy (ECT)-a preliminary study and multivariate approach. Comput Intell Neurosci. 2009;965209.
Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016;540:230–5.
Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, et al. Multi-sensory gamma stimulation ameliorates alzheimer’s-associated pathology and improves cognition. Cell. 2019;177:256–71 e222.
Xia J, Lu Z, Feng S, Yang J, Ji M. Different effects of immune stimulation on chronic unpredictable mild stress-induced anxiety- and depression-like behaviors depending on timing of stimulation. Int Immunopharmacol. 2018;58:48–56.
Kreisel T, Wolf B, Keshet E, Licht T. Unique role for dentate gyrus microglia in neuroblast survival and in VEGF-induced activation. Glia. 2018;67:594–618.
Mao XB, Ou MT, Karuppagounder SS, Kam TI, Yin XL, Xiong YL, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353:12.
Graydon CG, Mohideen S, Fowke KR. LAG3’s enigmatic mechanism of action. Front Immunol. 2020;11:615317.
Triebel F. LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination. Trends Immunol. 2003;24:619–22.
Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.
Rexach JE, Polioudakis D, Yin A, Swarup V, Chang TS, Nguyen T, et al. Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression. Cell Rep. 2020;33:108398.
Buisson S, Triebel F. LAG-3 (CD223) reduces macrophage and dendritic cell differentiation from monocyte precursors. Immunology. 2005;114:369–74.
Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci Transl Med. 2011;3:84ra43.
Reiber H, Felgenhauer K. Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chim Acta. 1987;163:319–28.
Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60.
Friedman A, Kaufer D, Shemer J, Hendler I, Soreq H, Tur-Kaspa I. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nat Med. 1996;2:1382–5.
Greene C, Hanley N, Campbell M. Blood-brain barrier associated tight junction disruption is a hallmark feature of major psychiatric disorders. Transl Psychiatry. 2020;10:373.
Niklasson F, Agren H. Brain energy metabolism and blood-brain barrier permeability in depressive patients: analyses of creatine, creatinine, urate, and albumin in CSF and blood. Biol Psychiatry. 1984;19:1183–206.
Kealy J, Greene C, Campbell M. Blood-brain barrier regulation in psychiatric disorders. Neurosci Lett. 2020;726:133664.
Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci. 2013;33:13820–33.
Grassivaro F, Menon R, Acquaviva M, Ottoboni L, Ruffini F, Bergamaschi A, et al. Convergence between microglia and peripheral macrophages phenotype during development and neuroinflammation. J Neurosci. 2020;40:784–95.
Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916–24.
Horikawa H, Kato TA, Mizoguchi Y, Monji A, Seki Y, Ohkuri T, et al. Inhibitory effects of SSRIs on IFN-gamma induced microglial activation through the regulation of intracellular calcium. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1306–16.
Hashioka S, Klegeris A, Monji A, Kato T, Sawada M, McGeer PL, et al. Antidepressants inhibit interferon-gamma-induced microglial production of IL-6 and nitric oxide. Exp Neurol. 2007;206:33–42.
Alboni S, Poggini S, Garofalo S, Milior G, El Hajj H, Lecours C, et al. Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment. Brain Behav Immun. 2016;58:261–71.
Hinwood M, Tynan RJ, Charnley JL, Beynon SB, Day TA, Walker FR. Chronic stress induced remodeling of the prefrontal cortex: structural re-organization of microglia and the inhibitory effect of minocycline. Cereb Cortex. 2012;23:1784–97.
Rimmerman N, Juknat A, Kozela E, Levy R, Bradshaw HB, Vogel Z. The non-psychoactive plant cannabinoid, cannabidiol affects cholesterol metabolism-related genes in microglial cells. Cell Mol Neurobiol. 2011;31:921–30.
Acknowledgements
We thank Ms. Zehava Cohen for help in preparation of the figures. We thank Dr. Gilgi Friedlander from the Nancy & Stephen Grand Israel National Center for Personalized Medicine (G-INCPM) for help with RNA-Seq and analysis. Postmortem brain tissue was donated by The Stanley Medical Research Institute brain collection. This research was supported by the Israel Science Foundation grant No. 1379/16 (to RY).
Author information
Authors and Affiliations
Contributions
NR and RY designed and directed the studies. HV, HG, LN, ER, EK RR, LA, SG, RR, EA, NS, LBH, CP, MA, ED, and KL performed the experiments. NR, HV, HG, LN, EK RR, KMR, DMM, ABZ, and RY analyzed the data. RY designed the concept and obtained funding. NR and RY wrote the manuscript.
Corresponding author
Ethics declarations
Competing interests
D.M.M. has received speaker’s honoraria from MECTA and Otsuka and an honorarium from Janssen for participating in an esketamine advisory board meeting. The other authors declare no competing financial interests in relation to the work in this paper.
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
Rimmerman, N., Verdiger, H., Goldenberg, H. et al. Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation. Mol Psychiatry 27, 1120–1135 (2022). https://doi.org/10.1038/s41380-021-01338-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-021-01338-0
This article is cited by
-
Systemic inflammatory biomarkers in Schizophrenia are changed by ECT administration and related to the treatment efficacy
BMC Psychiatry (2024)
-
Noteworthy perspectives on microglia in neuropsychiatric disorders
Journal of Neuroinflammation (2023)
-
Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway
Cellular and Molecular Life Sciences (2023)
-
Intranasal Monophosphoryl Lipid a Administration Ameliorates depression-like Behavior in Chronically Stressed Mice Through Stimulation of Microglia
Neurochemical Research (2023)
-
Inhibition of Microglial NLRP3 with MCC950 Attenuates Microglial Morphology and NLRP3/Caspase-1/IL-1β Signaling In Stress-induced Mice
Journal of Neuroimmune Pharmacology (2022)