Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia

• Type of Material: Article
• Authors: Courtney R. Sullivan, Taconic Biosciences; Catherine A. Mielnik, University of Toronto; Adam Funk, University of Toledo; Sinead M. O'Donovan, University of Toledo; Eduard Bentea, Vrije Universiteit Brussel; Mikhail Pletnikov, Johns Hopkins Medicine; Amy J. Ramsey, University of Toronto; Zhexing Wen, Emory University; Laura M. Rowland, University of Maryland; Robert E. McCullumsmith, University of Toledo
• Language: English
• Date: 2019-03-25
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-41572-9
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 5087
• End Page: 5087
• Keywords: NEURONS; Multidisciplinary Sciences; EXPRESSION; Science & Technology - Other Topics; ASTROCYTES; TRANSPORT; PH; METABOLISM; Science & Technology; SYNAPSES; MICE; DISC1; MITOCHONDRIAL DYSFUNCTION
• Research Categories: Biology, Neuroscience; Health Sciences, Mental Health

Abstract

Converging evidence suggests bioenergetic defects contribute to the pathophysiology of schizophrenia and may underlie cognitive dysfunction. The transport and metabolism of lactate energetically couples astrocytes and neurons and supports brain bioenergetics. We examined the concentration of lactate in postmortem brain (dorsolateral prefrontal cortex) in subjects with schizophrenia, in two animal models of schizophrenia, the GluN1 knockdown mouse model and mutant disrupted in schizophrenia 1 (DISC1) mouse model, as well as inducible pluripotent stem cells (iPSCs) from a schizophrenia subject with the DISC1 mutation. We found increased lactate in the dorsolateral prefrontal cortex (p = 0.043, n = 16/group) in schizophrenia, as well as in frontal cortical neurons differentiated from a subject with schizophrenia with the DISC1 mutation (p = 0.032). We also found a decrease in lactate in mice with induced expression of mutant human DISC1 specifically in astrocytes (p = 0.049). These results build upon the body of evidence supporting bioenergetic dysfunction in schizophrenia, and suggests changes in lactate are a key feature of this often devastating severe mental illness.