Molecular evidence of altered stress responsivity related to neuroinflammation in the schizophrenia midbrain.

Autor: Debs SR; Preclinical Neuropsychiatry Laboratory, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia; Discipline of Psychiatry & Mental Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, 2052, Australia., Rothmond DA; Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia., Zhu Y; Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY, 13210, USA., Weickert CS; Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia; Discipline of Psychiatry & Mental Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, 2052, Australia; Department of Neuroscience & Physiology, Upstate Medical University, Syracuse, NY, 13210, USA., Purves-Tyson TD; Preclinical Neuropsychiatry Laboratory, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia; Discipline of Psychiatry & Mental Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, 2052, Australia. Electronic address: t.purves-tyson@unsw.edu.au.
Jazyk: angličtina
Zdroj: Journal of psychiatric research [J Psychiatr Res] 2024 Sep; Vol. 177, pp. 118-128. Date of Electronic Publication: 2024 Jul 04.
DOI: 10.1016/j.jpsychires.2024.07.004
Abstrakt: Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of schizophrenia. Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in stress response pathways may occur in this region. To identify whether transcriptional changes in glucocorticoid and mineralocorticoid receptors (NR3C1/GR, NR3C2/MR) or other stress signalling molecules (FKBP4, FKBP5) exist in schizophrenia midbrain, we measured gene expression in the human brain (N = 56) using qRT-PCR. We assessed whether alterations in these mRNAs were related to previously identified high/low inflammatory status. We investigated relationships between stress-related transcripts themselves, and between FKBP5 mRNA, dopaminergic, and glial cell transcripts in diagnostic and inflammatory subgroups. Though unchanged by diagnosis, GR mRNA levels were reduced in high inflammatory compared to low inflammatory schizophrenia cases (p = 0.026). We found no effect of diagnosis or inflammation on MR mRNA. FKBP4 mRNA was decreased and FKBP5 mRNA was increased in schizophrenia (p < 0.05). FKBP5 changes occurred in high inflammatory (p < 0.001), whereas FKBP4 changes occurred in low inflammatory schizophrenia cases (p < 0.05). The decrease in mRNA encoding the main stress receptor (GR), as well as increased transcript levels of the stress-responsive negative regulator (FKBP5), may combine to blunt the midbrain response to stress in schizophrenia when neuroinflammation is present. Negative correlations between FKBP5 mRNA and dopaminergic transcripts in the low inflammatory subgroup suggest higher levels of FKBP5 mRNA may also attenuate dopaminergic neurotransmission in schizophrenia even when inflammation is absent. We report alterations in GR-mediated stress signalling in the midbrain in schizophrenia.
Competing Interests: Declaration of competing interest As required for submission of this manuscript to Journal of Psychiatric Research, we confirm that none of the authors listed on this manuscript have any conflicts of interest to declare.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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