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The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure.

ABSTRACT: Several intracellular pathways that contribute to the adaptation or maladaptation to environmental challenges mediate the vulnerability and resilience to chronic stress. The activity of the hypothalamic-pituitary-adrenal (HPA) axis is fundamental for the proper maintenance of brain processes, and it is related to the functionality of the isoform alfa and beta of the glucocorticoid receptor (Gr), the primary regulator of HPA axis. Among the downstream effectors of the axis, the scaffolding protein RACK1 covers an important role in regulating synaptic activity and mediates the transcription of the neurotrophin Bdnf. Hence, by employing the chronic mild stress (CMS) paradigm, we studied the role of the Grβ-RACK1-Bdnf signaling in the different susceptibility to chronic stress exposure. We found that resilience to two weeks of CMS is paralleled by the activation of this pathway in the ventral hippocampus, the hippocampal subregion involved in the modulation of stress response. Moreover, the results we obtained in vitro by exposing SH-SY5Y cells to cortisol support the data we found in vivo. The results obtained add novel critical information about the link among Gr, RACK1 and Bdnf and the resilience to chronic stress, suggesting novel targets for the treatment of stress-related disorders, including depression.

SUBMITTER: Brivio P

PROVIDER: S-EPMC8350424 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure.

Brivio Paola P Buoso Erica E Masi Mirco M Gallo Maria Teresa MT Gruca Piotr P Lason Magdalena M Litwa Ewa E Papp Mariusz M Fumagalli Fabio F Racchi Marco M Corsini Emanuela E Calabrese Francesca F

Neurobiology of stress 20210726

Several intracellular pathways that contribute to the adaptation or maladaptation to environmental challenges mediate the vulnerability and resilience to chronic stress. The activity of the hypothalamic-pituitary-adrenal (HPA) axis is fundamental for the proper maintenance of brain processes, and it is related to the functionality of the isoform alfa and beta of the glucocorticoid receptor (Gr), the primary regulator of HPA axis. Among the downstream effectors of the axis, the scaffolding protei ...[more]

PMID: 34401408

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Project description:RationaleThe accumulation of beta-amyloid peptide (Aβ) in the forebrain leads to cognitive dysfunction and neurodegeneration in Alzheimer's disease. Studies have shown that individuals with a consistently cognitively active lifestyle are less vulnerable to Aβ toxicity. Recent research has demonstrated that intrahippocampal Aβ can impact catecholaminergic release and spatial memory. Interestingly, exposure to novelty stimuli has been found to stimulate the release of catecholamines in the hippocampus. However, it remains uncertain whether repeated enhancing catecholamine activity can effectively alleviate cognitive impairment in individuals with Alzheimer's disease.ObjectivesOur primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aβ. This protection could be achieved by modulating catecholaminergic activity within the hippocampus.MethodsTo investigate this hypothesis, we subjected mice to three different conditions-standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aβ (Aβ1-42) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice.ResultsThe mice that received Aβ1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aβ1-42 intrahippocampal infusion. The stereological analysis indicated that the Aβ1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups.ConclusionsThese compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aβ1-42. They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.

Project description:Alternative splicing of the human glucocorticoid receptor gene generates two isoforms, hGRα and hGRβ. hGRβ functions as a dominant-negative regulator of hGRα activity and but also has inherent transcriptional activity, collectively altering glucocorticoid sensitivity. Single-nucleotide polymorphisms in the 3' UTR of hGRβ have been associated with altered receptor protein expression, glucocorticoid sensitivity, and disease risk. Characterization of the hGRβ G3134T polymorphism has been limited to a relatively small, homogenous population. The objective of this study was to determine the prevalence of hGRβ G3134T in a diverse population and assess the association of hGRβ G3134T in this population with physiological outcomes. In a prospective cohort study, 3730 genetically diverse participants were genotyped for hGRβ G3134T and four common GR polymorphisms. A subset of these participants was evaluated for clinical and biochemical measurements. Immortalized human osteosarcoma cells (U-2 OS), stably transfected with wild-type or G3134T hGRβ, were evaluated for receptor expression, stability, and genome-wide gene expression. Glucocorticoid-mediated gene expression profiles were investigated in primary macrophages isolated from participants. In a racially diverse population, the minor allele frequency was 74% (50.7% heterozygous carriers and 23.3% homozygous minor allele), with a higher prevalence in Caucasian non-Hispanic participants. After adjusting for confounding variable, carriers of hGRβ G3134T were more likely to self-report allergies, have higher serum cortisol levels, and reduced cortisol suppression in response to low-dose dexamethasone. The presence of hGRβ G3134T in U-2 OS cells increased hGR mRNA stability and protein expression. Microarray analysis revealed that the presence of the hGRβ G3134T polymorphism uniquely altered gene expression profiles in U-2 OS cells and primary macrophages. hGRβ G3134T is significantly present in the study population and associated with race, self-reported disease, and serum levels of glucocorticoids. Underlying these health differences may be changes in gene expression driven by altered receptor stability.

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The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure.

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The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure.

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