Dataset Information

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion.

ABSTRACT: Cystic fibrosis (CF) patients experience heightened levels of anxiety and depression. Stress from dealing with chronic disease and rigorous treatment regimens certainly are primary contributors to these outcomes. We previously have demonstrated that microtubule alterations in CF are linked to a number of CF phenotypes including growth regulation and inflammatory responses to airway bacterial challenge. Deletion of histone deactelyase 6 (HDAC6), a cytosolic deacetylase that regulates tubulin acetylation, in CF mice restores growth and inflammatory phenotypes to wild type (WT) profiles. In this study, the hypothesis that Hdac6 depletion in CF mice would impact behaviors since Hda6 inhibition has been previously reported to have anti-depressive properties. Data demonstrate that CF mice exhibit reduced activity and reduced open arm time in an elevated plus maze test which can be consistent with anxiety-like behavior. CF mice also exhibit depression-like behaviors compared to WT mice in an age dependent manner. By eight weeks of age, CF mice exhibit significantly more immobile time in the tail-suspension test, however, Hdac6 depletion reverses the depressive phenotype. These data demonstrate that loss of CFTR function may predispose patients to experience depression and that this behavior is Hdac6 dependent.

SUBMITTER: Corey DA

PROVIDER: S-EPMC7530985 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion.

Corey Deborah A DA Rymut Sharon M SM Kelley Thomas J TJ

Scientific reports 20201001 1

Cystic fibrosis (CF) patients experience heightened levels of anxiety and depression. Stress from dealing with chronic disease and rigorous treatment regimens certainly are primary contributors to these outcomes. We previously have demonstrated that microtubule alterations in CF are linked to a number of CF phenotypes including growth regulation and inflammatory responses to airway bacterial challenge. Deletion of histone deactelyase 6 (HDAC6), a cytosolic deacetylase that regulates tubulin acet ...[more]

PMID: 33004910

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Project description:BackgroundFrom the original CftrTgH(neoim)Hgu mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1) we have generated two inbred CftrTgH(neoim)Hgu mutant strains named CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu, which are fertile and show normal growth and lifespan. Initial genome wide scan analysis with microsatellite markers indicated that the two inbred strains differed on the genetic level. In order to further investigate whether these genetic differences have an impact on the disease phenotype of cystic fibrosis we characterised the phenotype of the two inbred strains.ResultsReduced amounts, compared to wild type control animals, of correctly spliced Cftr mRNA were detected in the nasal epithelia, lungs and the intestine of both inbred CftrTgH(neoim)Hgu strains, with higher residual amount observed for CF/1-CftrTgH(neoim)Hgu than CF/3-CftrTgH(neoim)Hgu for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-CftrTgH(neoim)Hgu and 4% for CF/3-CftrTgH(neoim)Hgu. Unlike the apparent strain and/or tissue specific regulation of Cftr mRNA splicing, short circuit current measurements in the respiratory and intestinal epithelium revealed that both strains have ameliorated the basic defect of cystic fibrosis with a presentation of a normal electrophysiology in both tissues.ConclusionUnlike the outbred CftrTgH(neoim)Hgu insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred CftrTgH(neoim)Hgu strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu offer an excellent model whereby determination of the minimal levels of protein required for the restoration of the basic defect of cystic fibrosis can be studied, along with the modulating factors which may affect this outcome.

Project description:Cystic fibrosis (CF) is caused by mutations in the CFTR gene that impair the function of CFTR, a cAMP-regulated anion channel. In the small intestine loss of CFTR function creates a dehydrated, acidic luminal environment which is believed to cause an accumulation of mucus, a phenotype characteristic of CF. CF mice have small intestinal bacterial overgrowth, an altered innate immune response, and impaired intestinal transit. We investigated whether lubiprostone, which can activate the CLC2 Cl- channel, would improve the intestinal phenotype in CF mice.Cftr(tm1UNC) (CF) and wildtype (WT) littermate mice on the C57BL/6J background were used. Lubiprostone (10 ?g/kg-day) was administered by gavage for two weeks. Mucus accumulation was estimated from crypt lumen widths in periodic acid-Schiff base, Alcian blue stained sections. Luminal bacterial load was measured by qPCR for the bacterial 16S gene. Gastric emptying and small intestinal transit in fasted mice were assessed using gavaged rhodamine dextran. Gene expression was evaluated by Affymetrix Mouse430 2.0 microarray and qRT-PCR.Crypt width in control CF mice was 700% that of WT mice (P < 0.001). Lubiprostone did not affect WT crypt width but, unexpectedly, increased CF crypt width 22% (P = 0.001). Lubiprostone increased bacterial load in WT mice to 490% of WT control levels (P = 0.008). Conversely, lubiprostone decreased bacterial overgrowth in CF mice by 60% (P = 0.005). Lubiprostone increased gastric emptying at 20 min postgavage in both WT (P < 0.001) and CF mice (P < 0.001). Lubiprostone enhanced small intestinal transit in WT mice (P = 0.024) but not in CF mice (P = 0.377). Among other innate immune markers, expression of mast cell genes was elevated 4-to 40-fold in the CF intestine as compared to WT, and lubiprostone treatment of CF mice decreased expression to WT control levels.These results indicate that lubiprostone has some benefits for the CF intestinal phenotype, especially on bacterial overgrowth and the innate immune response. The unexpected observation of increased mucus accumulation in the crypts of lubiprostone-treated CF mice suggests the possibility that lubiprostone increases mucus secretion.

Dataset Information

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion.

Publications

Alleviation of depression-like behavior in a cystic fibrosis mouse model by Hdac6 depletion.

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