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Profiling changes in cortical astroglial cells following chronic stress.

ABSTRACT: Recent studies have suggested that cortical astroglia play an important role in depressive-like behaviors. Potential astroglial contributions have been proposed based on their known neuroplastic functions, such as glutamate recycling and synaptic plasticity. However, the specific mechanisms by which astroglial cells may contribute or protect against a depressive phenotype remain unknown. To delineate astroglial changes that accompany depressive-like behavior, we used astroglial-specific bacTRAP mice exposed to chronic variable stress (CVS) and profiled the astroglial translatome using translating ribosome affinity purification (TRAP) in conjunction with RNAseq. As expected, CVS significantly increased anxiety- and depressive-like behaviors and corticosterone levels and decreased GFAP expression in astroglia, although this did not reflect a change in the total number of astroglial cells. TRAPseq results showed that CVS decreased genes associated with astroglial plasticity: RhoGTPases, growth factor signaling, and transcription regulation, and increased genes associated with the formation of extracellular matrices such as perineuronal nets (PNNs). PNNs inhibit neuroplasticity and astroglia contribute to the formation, organization, and maintenance of PNNs. To validate our TRAPseq findings, we showed an increase in PNNs following CVS. Degradation of PNNs in the prefrontal cortex of mice exposed to CVS reversed the CVS-induced behavioral phenotype in the forced swim test. These data lend further support to the neuroplasticity hypothesis of depressive behaviors and, in particular, extend this hypothesis beyond neuronal plasticity to include an overall decrease in genes associated with cortical astroglial plasticity following CVS. Further studies will be needed to assess the antidepressant potential of directly targeting astroglial cell function in models of depression.

SUBMITTER: Simard S

PROVIDER: S-EPMC6046043 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Profiling changes in cortical astroglial cells following chronic stress.

Simard Stephanie S Coppola Gianfilippo G Rudyk Christopher A CA Hayley Shawn S McQuaid Robyn J RJ Salmaso Natalina N

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180529 9

Recent studies have suggested that cortical astroglia play an important role in depressive-like behaviors. Potential astroglial contributions have been proposed based on their known neuroplastic functions, such as glutamate recycling and synaptic plasticity. However, the specific mechanisms by which astroglial cells may contribute or protect against a depressive phenotype remain unknown. To delineate astroglial changes that accompany depressive-like behavior, we used astroglial-specific bacTRAP ...[more]

PMID: 29907879

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Project description:Major depressive disorder (MDD) is a severe psychiatric disorder, characterized by deficits in GABAergic and glutamatergic signaling in cortical brain regions. Unpredictable chronic mild stress (UCMS), a murine stress model, induces behavioural and neurobiological changes reminiscent of MDD. Despite increasing knowledge of the cellular complexity of the cortical microcircuitry, our understanding of how distinct cell-types are impacted by UCMS is extremely limited. We thus endeavoured to determine the effect of UCMS on Pyramidal (PYR) cells and three classes of interneurons: Somatostatin (SST), Parvalbumin (PV), and Vasoactive intestinal peptide-expressing (VIP) cells in the medial prefrontal cortex. C57Bl/6 mice, exposed to UCMS or control housing for five weeks, were assessed with a battery of anxiety- and depressive-like behavioural tests. Laser-capture microdissection was used to isolate samples of microcircuit cell-types, which underwent RNA-sequencing. UCMS-exposed mice showed significantly elevated emotionality, and isolate cell-types showed robust specificity. Cell-types exhibited unique transcriptomic profiles after UCMS. Briefly, PYR-cells showed decreased signaling and post-synaptic receptor expression, SST-cells showed increased activation of the unfolded protein response, PV-cells showed increased axonal microtubule expression, and VIP-cells showed increased apoptotic signaling and altered cytoskeletal gene expression. Co-expression analyses revealed that these changes were largely correlated across cell-types and that UCMS increased transcriptome-wide co-expression between PYR and both PV and SST cells. Overall, these findings suggest decreased PYR, SST, and VIP-cell function, elevated PV-cell function, and identify the dysregulation of PYR-cells as a central locus of UCMS-induced transcriptomic change. Further studies interrogating potential antidepressant-like activity of compounds reversing these cell-specific changes are warranted.

Project description:Astrocytes are taking the center stage in neurotrauma and neurological diseases as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting NF-?B activation in astrocytes, using a transgenic mouse model (GFAP-I?B?-dn mice), results in improved functional recovery, increased white matter preservation and axonal sparing following spinal cord injury (SCI). In the present study, we sought to determine whether this improvement, due to inhibiting NF-?B activation in astrocytes, could be the result of enhanced oligodendrogenesis in our transgenic mice.To assess oligodendrogenesis in GFAP-I?B?-dn compared to wild-type (WT) littermate mice following SCI, we used bromodeoxyuridine labeling along with cell-specific immuno-histochemistry, confocal microscopy and quantitative cell counts. To further gain insight into the underlying molecular mechanisms leading to increased white matter, we performed a microarray analysis in naïve and 3 days, 3 and 6 weeks following SCI in GFAP-I?B?-dn and WT littermate mice.Inhibition of astroglial NF-?B in GFAP-I?B?-dn mice resulted in enhanced oligodendrogenesis 6 weeks following SCI and was associated with increased levels of myelin proteolipid protein compared to spinal cord injured WT mice. The microarray data showed a large number of differentially expressed genes involved in inflammatory and immune response between WT and transgenic mice. We did not find any difference in the number of microglia/leukocytes infiltrating the spinal cord but did find differences in their level of expression of toll-like receptor 4. We also found increased expression of the chemokine receptor CXCR4 on oligodendrocyte progenitor cells and mature oligodendrocytes in the transgenic mice. Finally TNF receptor 2 levels were significantly higher in the transgenic mice compared to WT following injury.These studies suggest that one of the beneficial roles of blocking NF-?B in astrocytes is to promote oligodendrogenesis through alteration of the inflammatory environment.

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Profiling changes in cortical astroglial cells following chronic stress.

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Profiling changes in cortical astroglial cells following chronic stress.

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