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Altered mRNA Levels of Glucocorticoid Receptor, Mineralocorticoid Receptor, and Co-Chaperones (FKBP5 and PTGES3) in the Middle Frontal Gyrus of Autism Spectrum Disorder Subjects

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Abstract

Although stress has been implicated in the pathophysiology of autistic spectrum disorder (ASD), it is not known whether glucocorticoid receptor (GR) levels are altered in the brain of subjects with ASD. The messenger RNA (mRNA) levels of GR isoforms (GRα, GRβ, GRγ, and GRP), mineralocorticoid receptor (MR), GR co-chaperones (FKBP5, PTGES3, and BAG1), and inflammatory cytokines (IL-6, IL-1β, and IFN-γ) were examined in the postmortem middle frontal gyrus tissues of 13 ASD and 13 age-matched controls by qRT-PCR. The protein levels were examined by Western blotting. We found significant decreases in GRα (64 %), GRγ (48 %), GRP (20 %) and MR (46 %) mRNA levels in ASD subjects as compared to controls. However, significant increases in FKBP5 (42 %) and PTGES3 (35 %) mRNA levels were observed in ASD subjects. There were no differences in the mRNA levels of GRβ and BAG1 in ASD subjects as compared to controls. MR mRNA was found to be negatively correlated with the diagnostic score for abnormality of development. On the protein level, significant reductions in GR and MR, but no change in FKBP5 and PTGES3 were found in ASD subjects as compared to controls. Moreover, we observed significant increases in IL-1β and IFN-γ mRNA levels in ASD subjects, and these cytokines were negatively associated with GR levels. Our data, for the first time, reports dysregulation of GR, MR, FKBP5, and PTGES3 in ASD and suggest a possible role of inflammation in altered GR function in ASD.

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Abbreviations

ADI-R:

Autism diagnostic interview revised

ASD:

Autism spectrum disorders

BAG1:

BCL2-associated athanogene

GRα:

Glucocorticoid receptor alpha

FKBP5:

FK506 binding protein 51

IFN-γ:

Interferon-gamma

IL-1β:

Interleukin-1beta

IL-6:

Interleukin-6

GRβ:

Glucocorticoid receptor beta

GRγ:

Glucocorticoid receptor gamma

GRP:

Glucocorticoid receptor P

PTGES3:

Prostaglandin E synthase 3 (cytosolic)

MR:

Mineralocorticoid receptor

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Acknowledgments

The authors would like to thank Diya Peter for her technical assistance. Human postmortem samples were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. The Bank is funded by NIH Contract No. #HHSN275200900011C, Ref. No. NO1-HD-9-0011.

Conflict of Interest

The author(s) declare that they have no competing interests.

Author Contributions

NP and AC carried out the gene expression studies. CDP and AC performed the protein analysis. AOA carried out the statistical analysis and helped to draft the manuscript. AP designed the study and wrote the manuscript. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, 997 St. Sebastian Way, Augusta, GA, 30912, USA

    Neil Patel, Amanda Crider, Chirayu D. Pandya & Anilkumar Pillai

  2. Department of Psychiatry, Weill Cornell Medical College, 21 Bloomingdale Rd, White Plains, NY, 10605, USA

    Anthony O. Ahmed

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  1. Neil Patel
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  2. Amanda Crider
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  3. Chirayu D. Pandya
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Correspondence to Anilkumar Pillai.

Additional information

Neil Patel and Amanda Crider are co-first authors.

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Additional file 1: Table S1

List of primers used in the qRT-PCR. (DOCX 15 kb)

Additional file 2: Table S2

Correlations of mRNA transcripts with confounding variables. (DOCX 15 kb)

Additional file 3: Table S3

Correlations between stress-related mRNA transcripts. (DOCX 18 kb)

Additional file 4: Table S4

Correlation between cytokine and stress-related mRNA transcripts. (DOCX 14 kb)

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Patel, N., Crider, A., Pandya, C.D. et al. Altered mRNA Levels of Glucocorticoid Receptor, Mineralocorticoid Receptor, and Co-Chaperones (FKBP5 and PTGES3) in the Middle Frontal Gyrus of Autism Spectrum Disorder Subjects. Mol Neurobiol 53, 2090–2099 (2016). https://doi.org/10.1007/s12035-015-9178-2

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