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Electroconvulsive Stimulation modulates Microglia. Transcriptome analysis of Biozzi-ABH mice spinal-cord microglia following electroconvulsive-seizures.

ABSTRACT: Neurostimulation by electroconvulsive therapy is highly effective in neuropsychiatric disorders by an unknown mechanism. Microglial toxicity plays a key role in chronic neuro-inflammatory brain diseases, where there is critical shortage in therapies. To investigate the direct effect of electroconvulsive seizures (ECS) on the CNS innate immune system, we performed transcriptome analysis on spinal microglia from ECS- and sham-treated naïve mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE137184 | GEO | 2022/09/01

REPOSITORIES: GEO

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Project description:Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e. fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ~50–63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-days chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n=18), or Flx non-responder mice (Flx-NR, n=7). Then, Flx-NR mice received 7 sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down- and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology. remark for sample name : ECTR=Flx-NR-ES, C=cort/Veh, CFNR= Flx-NR

Project description:Rationale Electroconvulsive seizure (ECS) therapy is a nonchemical treatment for depression. Since ECS up-regulates expression of c-Fos in the paraventricular nucleus of hypothalamus (PVN), the function of which is frequently influenced in depression, we hypothesized that ECS modulates functions of the PVN and contributes to its antidepressant effects. Objectives To identify gene expression changes in the mouse PVN by ECS treatment Material and methods First, we established a method to amplify nucleotides from small quantities of RNA. Mice received one shock of ECS and their brains were collected at 2 or 6 h after shock. The PVN was microdissected from dehydrated brain sections, its total RNA was extracted and microarray analysis was applied. Results At 2 h after ECS, 2.6% (589 genes) of the probes showed more than 2-fold decrease, and 0.9% (205 genes) showed more than 2-fold increase. To confirm the expression changes, genes showing differential expression with a wide range in the microarray were analyzed by qPCR. Among the genes with more than 2-fold change by ECS, down-regulated 94 genes and up-regulated 24 genes have been reported the association with anxiety, bipolar disorder or mood disorder by the Ingenuity knowledge database. The groups of down-regulated genes, which are suggested to modulate the function of the PVN or associate to psychiatric disorders, include neuropeptides (Cck), kinases (Prkcb, Prkcc, Camk2a), transcription factors (Bcl6, Tbr1), transporters (Aqp4) and others (Fmr1). Conclusion The present results indicate that ECS treatment can modulate the functions of PVN via a series of gene expression changes, and may contribute to its antidepressant effects at least in part. Mice received one shock of ECS and their brains were collected at 2 h (PVN_ECS2h_1, PVN_ECS2h_2) or 6 h after shock (PVN_ECS6h_1, PVN_ECS6h_2). The brains of sham-treated animals were collected at 2 h after treatment (PVN_sham_1, PVN_sham_2). The PVN was microdissected from dehydrated brain sections, and its total RNA was extracted. RNA samples from two or three animals were pooled to minimize the impact of biological variance. After nucleotide amplification by the ovation amplification, the gene expression profiles were obtained by the Affymetrix microarray analysis. The microarray analysis was performed twice using different sets of animals.

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Electroconvulsive Stimulation modulates Microglia. Transcriptome analysis of Biozzi-ABH mice spinal-cord microglia following electroconvulsive-seizures.

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