Dysfunction of mitochondria and GABAergic interneurons in the anterior cingulate cortex of individuals with schizophrenia

Mari A Kondo; Alexis L Norris; Kun Yang; Madeline Cheshire; Isabelle Newkirk; Xiangning Chen; Koko Ishizuka; Andrew E Jaffe; Akira Sawa; Jonathan Pevsner

doi:10.1016/j.neures.2022.09.011

Dysfunction of mitochondria and GABAergic interneurons in the anterior cingulate cortex of individuals with schizophrenia

Neurosci Res. 2022 Dec:185:67-72. doi: 10.1016/j.neures.2022.09.011. Epub 2022 Sep 23.

Authors

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America.
² Department of Neurology, Kennedy Krieger Institute, Baltimore, MD, the United States of America; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America.
³ Department of Neurology, Kennedy Krieger Institute, Baltimore, MD, the United States of America.
⁴ Nevada Institute of Personalized Medicine and Department of Psychology, University of Nevada, Las Vegas, NV, the United States of America.
⁵ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, the United States of America; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, the United States of America.
⁶ Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, the United States of America; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America; Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America; Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America.
⁷ Department of Neurology, Kennedy Krieger Institute, Baltimore, MD, the United States of America; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, the United States of America. Electronic address: jonathan.pevsner@nih.gov.

PMID: 36162734
DOI: 10.1016/j.neures.2022.09.011

Abstract

Here we re-analyze RNA-sequencing data from the anterior cingulate cortex (ACC) of SZ patients using recent methods to improve accuracy and sensitivity of results, such as the quality surrogate variable analysis (qSVA) method and the derfinder R package. We found that genes significantly down-regulated in SZ demonstrated an enrichment for parvalbumin-positive interneurons (FDR < 0.0001). Down-regulated genes were also enriched in oxidative phosphorylation functions (FDR < 0.05). We also addressed whether lifetime exposure to antipsychotics might influence gene expression, highlighting DUSP6, LBH, and NR1D1. Our results support the role of redox imbalance/mitochondrial dysfunction and implicate interneuron subtypes in SZ pathophysiology.

Keywords: Anterior cingulate cortex; Gene expression; Mitochondrial dysfunction; Quality surrogate variable analysis; Redox imbalance; Schizophrenia.

MeSH terms

Gyrus Cinguli*
Humans
Interneurons / metabolism
Mitochondria / metabolism
Parvalbumins / metabolism
Schizophrenia* / genetics

Substances

Parvalbumins