Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation

Rimmerman, Neta; Verdiger, Hodaya; Goldenberg, Hagar; Naggan, Lior; Robinson, Elad; Kozela, Ewa; Gelb, Sivan; Reshef, R.; Ryan, Karen M.; Ayoun, L.; Refaeli, Ron; Ashkenazi, Einat; Schottlender, Nofar; Hemo-Cohen, Laura Ben; Pienica, Claudia; Aharonian, Maayan; Dinur, Eyal; Lazar, K.; McLoughlin, Declan M.; Zvi, Ayal Ben; Raz, Yael

doi:10.1038/s41380-021-01338-0

Cited by 35 publications

(13 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that anti-in ammatory factor IL-4 was elevated after 9 times of ECT and negatively correlated with BPRS (Brief Psychiatric Rating Scale), although the expression levels of NF-KB, a major pathway involved in the immune in ammatory response, did not change 42 . Although not animal models of schizophrenia, a recent study showed that the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), was the only microglial transcript signi cantly reduced by ECS (electroconvulsive stimulation) 43 . Our results showed lymphocytes were signi cantly higher in remitters, while PLR was signi cantly lower in remitters.…”

Section: Discussionmentioning

confidence: 99%

Altered concentrations of systemic inflammatory biomarkers after electroconvulsive therapy in schizophrenia and their relationship with treatment

Wang

Gong

et al. 2023

Preprint

View full text Add to dashboard Cite

Background and hypothesis: Platelet count (PLT), neutrophils, lymphocytes, monocytes and three important ratios calculated from them: NLR, PLR and MLR are inexpensive and accessible biomarkers of systemic inflammation. Electroconvulsive therapy (ECT) is a rapid and effective physical therapy for schizophrenia, but the exploration of its therapeutic mechanisms is still in the early stages. Here we hypothesized the concentrations of systemic inflammatory biomarkers are higher in schizophrenia and decreased after electroconvulsive therapy. Elevated systemic inflammatory biomarkers were associated with less improvement in psychiatric symptoms and cognitive function after ECT. Study design: This study included 70 patients with schizophrenia (all patients have been treated with antipsychotic medication for a fortnight before ECT) as well as age- and sex-matched 70 healthy controls. We compared the differences of systemic inflammatory biomarkers between schizophrenia and healthy controls, and then determined the changes of systemic inflammatory biomarkers in schizophrenia before and after 6 times of electroconvulsive therapy. Positive and negative symptom scale (PANSS) were used to measure psychiatric symptom of patients with schizophrenia, and Mini-Mental State Examination (MMSE) were used to measure the cognitive function. Spearman correlation analysis was used to assess the relationship between systemic inflammatory biomarkers and clinical symptoms. Results: At baseline, peripheral blood PLT, neutrophils, monocytes and three important ratios: NLR, PLR and MLR were significantly higher in patients with schizophrenia than in healthy controls (all P<0.05), while lymphocytes did not differ between the two groups. After 6 ECT, neutrophils and NLR significantly decreased, and there was a downward trend in monocytes and MLR. Although PLR and lymphocytes were unchanged after ECT, lymphocytes were significantly higher in remitters than in the non-remitters, and PLR was significantly lower than in the non-remitters. Moreover, the higher the baseline NLR, PLR and MLR, the less improvement in positive symptoms after ECT; and the higher the baseline monocytes, the worse the cognitive function after ECT. Lymphocytes as a protective factor, although unchanged before and after ECT, were negatively associated with total PANSS score, positive symptom score and positively associated with reduction rate of PANSS after ECT. Conclusions: Our results further emphasize the presence of systemic inflammation in schizophrenia and that electroconvulsive therapy may exert a therapeutic effect in part by attenuating systemic inflammation in schizophrenia. Thus, further studies may lead to new treatment strategies for schizophrenia targeting immune system.

show abstract

Section: Discussionmentioning

confidence: 99%

Altered concentrations of systemic inflammatory biomarkers after electroconvulsive therapy in schizophrenia and their relationship with treatment

Wang

Gong

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Additionally, in mice exhibiting depressive-like symptoms, treatment with immunostimulatory drugs or electroconvulsive therapy (ECT, which is usually given in a more chronic phase with non-response to initial antidepressants) restored normal microglia morphology and demonstrated microglia-stimulating effects. 12 , 13 …”

Section: Temporal Effects Of Depression On Microgliamentioning

confidence: 99%

Reporting Psychiatric Disease Characteristics in Post-Mortem- and Biological Research

Scheepstra,

Mizee,

Wever

et al. 2024

J Exp Neurosci

View full text Add to dashboard Cite

Inflammation is a prominent hypothesis in the neurobiology of depression. In our transcriptomic profiling study of microglia in chronic major depressive disorder (MDD), we revealed a distinct disease-associated microglia (DAM) transcriptomic profile exclusively found in cortical gray matter, that we have designated DepDAM. These DepDAM revealed an immune-suppressed state, with a possible upstream mechanism for microglial suppression, by upregulation of CD200 and CD47 (“don’t eat me signals”) located on synapses. We extensively report on disease characteristics, such as cause of death, reason for euthanasia, and psychiatric state when deceased. When excluding MDD donors in a euthymic state, the trend of lower CD45 membrane expression on white matter microglia became significant, and the difference in gray matter microglia became larger. For Western blot analysis of CD47 and CD200, both means of the definitely depressed donor groups (MDD-D) increased. This underscores the utmost importance of reporting on patient and episode characteristics, such as severity, episode traits, (type of) suicidality, mode of decease, and state of illness at death in post-mortem- and biological psychiatric research. For psychiatric post-mortem research, we suggest using well-characterized donors (eg, after “psychological autopsy”) selected by an experienced clinician.

show abstract

“…Microglia play an essential role in synaptic circuit remodeling and phagocytosis of synaptic material, and defects may contribute to synaptic abnormalities seen in both neurodevelopmental and neurodegenerative diseases (45,46). Pre-clinical studies in depressed-like rodents showed microglial depletion with attenuated antidepressant and neurogenesisenhancing treatment effects with imipramine or electroconvulsive stimulation (47). Also, microglial stimulation in chronic unpredictable stress-exposed mice with lipopolysaccharide or macrophage colony-stimulating factor reversed depressed-like behavior (48).…”

Section: Increased Suppression Of Microglia In Mdd Gmmentioning

confidence: 99%

Microglia transcriptional profiling in major depressive disorder shows inhibition of cortical grey matter microglia

Scheepstra

Mizee

Scheppingen

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains. Methods: Pure, viable microglia were isolated at brain autopsy from occipital cortex grey matter (GM) and corpus callosum white matter (WM) of 13 MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry (IHC) staining. Since gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by RT-qPCR and Western blot. Results: Transcriptome analysis revealed 92 genes that were differentially expressed in GM microglia of MDD, but none in WM, when compared to control, of which 81 were less abundantly expressed in GM MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis were differentially regulated in GM microglia in MDD. IHC staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue showed an increase in CD200 (p<0.001) and CD47 (p=0.068) mRNA, and CD47 protein was significantly elevated (p<0.05) in synaptic fractions. Conclusions: Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD, possibly caused by neuronal regulation.

show abstract

Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation

Cited by 35 publications

References 118 publications

Altered concentrations of systemic inflammatory biomarkers after electroconvulsive therapy in schizophrenia and their relationship with treatment

Altered concentrations of systemic inflammatory biomarkers after electroconvulsive therapy in schizophrenia and their relationship with treatment

Reporting Psychiatric Disease Characteristics in Post-Mortem- and Biological Research

Microglia transcriptional profiling in major depressive disorder shows inhibition of cortical grey matter microglia

Contact Info

Product

Resources

About