Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue

Rajkowska, Grażyna; Stockmeier, Craig A.

doi:10.2174/13894501113149990156

Cited by 496 publications

(401 citation statements)

References 204 publications

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“…Glial cells account for at least 75% of brain cells 1 , and are implicated in a range of psychiatric disorders, including alcoholism 2 , schizophrenia 3 , depression 4 and suicide 5,6 . In particular, astrocytic dysfunction is evident in depressive psychopathologies, including suicide 4 .…”

Section: Introductionmentioning

confidence: 99%

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Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

et al. 2014

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Astrocytes are glial cells specific the central nervous system involved in numerous brain functions including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1, and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared to 17 matched controls using MBD2-sequencing followed by validation with high resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, GRIK2 and BEGAIN were the most significant, and also significantly correlated with genes expression. Cell sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN.Functional cell assays revealed promoter and enhancer-like properties in this region, which were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known ENCODE identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype.

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Section: Introductionmentioning

confidence: 99%

“…In particular, astrocytic dysfunction is evident in depressive psychopathologies, including suicide 4 . Astrocytes are multifaceted cells with numerous functions, including regulation of blood flow, synaptic communication and plasticity, immune regulation 7 and maintenance of neuronal functioning 8 .…”

Section: Introductionmentioning

confidence: 99%

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

et al. 2014

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“…In addition to these analyses of the changes in brain function underlying depression, region-specific metabolic changes as derived from MRS have been reported for depressed patients (Hasler et al, 2007). These metabolic changes could be related to altered neuronal and glial function (Harrison, 2002;Rajkowska and Stockmeier, 2013;Yuksel and Ongur, 2010).…”

Section: Introductionmentioning

confidence: 99%

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

et al. 2016

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Human depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward. Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a post-treatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in between-network FC, including amygdala -prefrontal cortex and amygdala -cingulate cortex. MRS identified metabolic alterations in CPS mice as increased inositol levels in amygdala and increased glycerophosphorylcholine levels in prefrontal cortex. Diffusion-weighted MRI detected increased fractional anisotropic values in the cingulum. This study demonstrates that chronic psychosocial stress induces FC states in the mouse brain analogous to those observed in depression, as well as cerebral metabolism and white matter pathway alterations that contribute to understanding of pathological processes. It also demonstrates the importance of brain imaging to the establishment of valid animal models in translational psychiatry. AbstractHuman depression, for which chronic psychosocial stress is a major risk factor, is characterized by consistent alterations in neurocircuitry. For example, there is increased functional connectivity (FC) within and between regions comprising the default mode network (DMN) including prefrontal cortex and cingulate cortex. Alterations in network FC are associated with specific aspects of psychopathology. In mice, chronic psychosocial stress (CPS) leads to depression-relevant behavior, including increased fear learning, learned helplessness, fatigue and decreased motivation for reward.Using multimodal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS), we investigated CPS effects on function and structure in the mouse brain under light anesthesia. Mice underwent a baseline MRI/MRS session, followed by 15-day CPS (n=26) or control handling (n=27), and a posttreatment MRI/MRS session. In BOLD fMRI, relative to controls, CPS mice exhibited robust, reproducible increases in FC within 8 of 9 identified cortical networks, including the prefrontal and cingulate cortices that contribute to the "mouse DMN". CPS mice exhibited increases in b...

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“…The number of astrocytes, and expression of astrogliotic marker GFAP both are significantly decreased in the brains of depressed patients (McNally et al 2008;Rajkowska et al 2013). At the same time treatment with antidepressants increases GFAP levels (Barley et al 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Expression of another astroglial marker, the calcium-binding protein S100β has been reduced in the ventral prefrontal cortex of depressed suicide victims (Klempan et al 2009). Several other astroglial markers, such as aquaporin 4, astroglial connexins, astroglial plasmalemmal glutamate transporters and glutamine synthetase are all down-regulated in mood disorders (Rajkowska et al 2013;Barley et al 2009;Bernard et al 2011;Sequeira et al 2009). Reduced number of astrocytes and of their packing density was detected throughout the fronto-limbic areas of the brain, including the orbito-frontal area, and anterior cingulate, prefrontal, entorhinal and subgenual cortices, as well as the amygdala (Rajkowska et al 2013;Verkhratsky et al 2014;Popoli et al 2011;Sanacora et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine

Bai

Song

et al. 2017

Psychopharmacology

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Here we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations fluoxetine down-regulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.

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Astrocyte Pathology in Major Depressive Disorder: Insights from Human Postmortem Brain Tissue

Cited by 496 publications

References 204 publications

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

Astrocytic abnormalities and global DNA methylation patterns in depression and suicide

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine

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