Astroglial Plasticity in the Hippocampus is Affected by Chronic Psychosocial Stress and Concomitant Fluoxetine Treatment

Czéh, Boldizsár; Simon, Mária; Schmelting, Barthel; Hiemke, Christoph; Fuchs, Eberhard

doi:10.1038/sj.npp.1300982

Cited by 393 publications

(272 citation statements)

References 73 publications

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“…The antidepressant treatment had no effects on the shrinkage of somal volume. These changes of astroglial structural plasticity in response to stress and antidepressant treatment support the notion that glial changes may contribute to the pathophysiology of affective disorders as well as the cellular activity of antidepressants (Czeh et al 2006;Manev et al 2003).…”

Section: Paroxetine-induced Effects On Glial Cells-implications For Nsupporting

confidence: 73%

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

et al. 2008

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Introduction Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve-indicating the involvement of effects distant from reuptake inhibition. Objective To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression. Materials and methodsThe behavioral response to longterm paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology. Results and discussion Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice. Conclusion Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.

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Section: Paroxetine-induced Effects On Glial Cells-implications For Nsupporting

confidence: 73%

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

et al. 2008

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“…According to the type 1/type 2 hypothesis of astrocytes and microglia, stress is associated with microglia activation, but also with a loss in the number and volume of astrocytes. 154 Animal studies show that stress induces an enhanced expression of proinflammatory factors such as IL-1b, 155,156 macrophage migration inhibitory factor [157][158][159] and COX-2 160 in the brain. Elevation of these proinflammatory factors is accompanied with dendritic atrophy and neuronal death within the hippocampus, 161,162 which are also found in brains of subjects with MD.…”

Section: Stress and Cns Immune Systemmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…Fluoxetine and its pharmacologically active metabolite norfluoxetine were determined in blood plasma samples collected at the end of each experiment, as described in detail previously (Czéh et al, 2006). We used a highperformance liquid chromatography (HPLC) method with column switching and ultraviolet (UV) spectrophotometric detection at 210 nm as described for the antipsychotic drug, amisulpride (Sachse et al, 2003).…”

Section: Analysis Of Fluoxetine and Norfluoxetinementioning

confidence: 99%

“…The functional significance of these observations is not clear, but recent theories suggest that glial cell dysfunction may contribute to the pathogenesis of affective disorders (Coyle and Schwarcz, 2000;Cotter et al, 2001b). Moreover, there is experimental evidence indicating that stress and antidepressant treatment can induce changes in structural plasticity of astrocytes and NG2-positive glia (Czéh et al, 2006;Wennström et al, 2006). The majority of the post mortem histopathological studies on glial reduction in frontolimbic structures have not identified which populations of glial cells are reduced, but there is an indication of the involvement of both astrocytes and oligodendrocytes (Cotter et al, 2001b;Rajkowska, 2003).…”

Section: Phenotypic Analysis Of the Newborn Cellsmentioning

confidence: 99%

Chronic Social Stress Inhibits Cell Proliferation in the Adult Medial Prefrontal Cortex: Hemispheric Asymmetry and Reversal by Fluoxetine Treatment

Czéh

Müller-Keuker

Ryguła

et al. 2006

Neuropsychopharmacol

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Profound neuroplastic changes have been demonstrated in various limbic structures after chronic stress exposure and antidepressant treatment in animal models of mood disorders. Here, we examined in rats the effect of chronic social stress and concomitant antidepressant treatment on cell proliferation in the medial prefrontal cortex (mPFC). We also examined possible hemispheric differences. Animals were subjected to 5 weeks of daily social defeat by an aggressive conspecific and received concomitant, daily, oral fluoxetine (10 mg/kg) during the last 4 weeks. Bromodeoxyuridine (BrdU) labeling and quantitative stereological techniques were used to evaluate the treatment effects on proliferation and survival of newborn cells in limbic structures such as the mPFC and the hippocampal dentate gyrus, in comparison with nonlimbic structures such as the primary motor cortex and the subventricular zone. Phenotypic analysis showed that neurogenesis dominated the dentate gyrus, whereas in the mPFC most newborn cells were glia, with smaller numbers of endothelial cells. Chronic stress significantly suppressed cytogenesis in the mPFC and neurogenesis in the dentate gyrus, but had minor effect in nonlimbic structures. Fluoxetine treatment counteracted the inhibitory effect of stress. Hemispheric comparison revealed that the rate of cytogenesis was significantly higher in the left mPFC of control animals, whereas stress inverted this asymmetry, yielding a significantly higher incidence of newborn cells in the right mPFC. Fluoxetine treatment abolished hemispheric asymmetry in both control and stressed animals. These pronounced changes in gliogenesis after chronic stress exposure may relate to the abnormalities of glial cell numbers reported in the frontolimbic areas of depressed patients.

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Astroglial Plasticity in the Hippocampus is Affected by Chronic Psychosocial Stress and Concomitant Fluoxetine Treatment

Cited by 393 publications

References 73 publications

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Chronic Social Stress Inhibits Cell Proliferation in the Adult Medial Prefrontal Cortex: Hemispheric Asymmetry and Reversal by Fluoxetine Treatment

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