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Bioenergetic Abnormalities in Schizophrenia

Sullivan, Courtney R
http://orcid.org/0000-0001-9267-1060
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1523629996205968

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Schizophrenia is a devastating illness that displays a wide range of psychotic symptoms, as well as cognitive deficits and profound negative symptoms that are often treatment resistant. Cognition is intimately related to synaptic function, which relies on the ability of cells to obtain adequate amounts of energy. Studies have shown that disrupting bioenergetic pathways affects working memory and other cognitive behaviors. Thus, investigating bioenergetic function in schizophrenia could provide important insights into treatments or prevention of cognitive disorders. Therefore, we characterized a major pathway supplying energy to neurons (lactate shuttle) in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. We found a significant decrease in the activity of two key glycolytic enzymes in schizophrenia (hexokinase and phosphofructokinase), suggesting a decrease in the capacity to generate bioenergetic intermediates through glycolysis in this illness. Notably, we did not detect protein changes in enzymes or transporters in this pathway in the DLPFC, suggesting the bioenergetic interplay of astrocytes and neurons in schizophrenia is highly complex and may not be fully appreciated at the region-level. Thus, we utilized a cell-level approach (laser capture microdissection) and found significant mRNA changes in glycolytic enzymes (hexokinase-1, phosphofructokinase-muscle, phosphofructokinase-liver, and glucose-6-phosphate isomerase), lactate transporters (monocarboxylate transporter 1), and glucose transporters (glucose transporter 1, GLUT1 and GLUT3) in pyramidal neurons in schizophrenia. We did not find any changes in astrocytes, suggesting neuron-specific deficits in glycolytic pathways in the DLPFC in schizophrenia. To build on these findings, we performed bioinformatic analyses to examine the implications of an altered bioenergetic profile in schizophrenia. We first sought to replicate our findings in additional cohorts of schizophrenia and control subjects. We probed 2 independent transcriptomic datasets for our metabolic targets. Supporting our hypothesis, we found several glycolytic targets to also be dysregulated in schizophrenia in these databases. Using the Library of Integrated Network-Based Cellular Signatures (LINCS) database to generate transcriptional signatures containing differentially expressed genes associated with bioenergetic abnormalities in schizophrenia. Using these signatures, we performed enrichment analyses to examine biological significance and found hits for cell metabolism, proliferation, and immunity/inflammation pathways. Furthermore, we compared our disease signatures to a library of “drug activity transcriptional signatures” to identify possible perturbagens with the ability to “reverse” the disease signature. Top perturbagens included peroxisome proliferator-activated receptor (PPAR) agonists, capable of bolstering metabolic pathways and possibly reversing cognitive deficits. To further elucidate the role of bioenergetics in cognitive dysfunction, we utilized the GluN1 knockdown (KD) model of schizophrenia. This model exhibits several endophenotypes of schizophrenia including impairments in executive function. With the goal of reversing these deficits, we selected a top perturbagen from our drug discovery bioinformatic analysis with the hypothesis that this drug intervention may help restore schizophrenia endophenotypes in this model. We investigated the effects of pioglitazone treatment, a ligand for PPARγ in the GluN1 KD model and found that pioglitazone helped restore explicit memory. This suggests pioglitazone may improve specific subtypes of cognition. This work has important implications for the treatment of cognitive illnesses with bioenergetic deficits such as schizophrenia.
Mark Baccei, Ph.D. (Committee Chair)
Temugin Berta (Committee Member)
Michael Lieberman, Ph.D. (Committee Member)
Robert McCullumsmith, M.D. (Committee Member)
Robert McNamara, Ph.D. (Committee Member)
239 p.
Neurology
schizophrenia; bioenergetics; glycolysis; GluN1 knockdown mouse; LINCS bioinformatics; pioglitazone

Recommended Citations

Citations

  • Sullivan, C. R. (2018). Bioenergetic Abnormalities in Schizophrenia [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1523629996205968

    APA Style (7th edition)

  • Sullivan, Courtney. Bioenergetic Abnormalities in Schizophrenia. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1523629996205968.

    MLA Style (8th edition)

  • Sullivan, Courtney. "Bioenergetic Abnormalities in Schizophrenia." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1523629996205968

    Chicago Manual of Style (17th edition)

ucin1523629996205968
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This open access ETD is published by University of Cincinnati and OhioLINK.