Schizophrenia (SZ) is a debilitating mental illness typically developing after puberty. Accumulating evidence suggests role for disturbances in postnatal brain maturation, which includes interneuron deficits. However, mechanistic understanding of SZ is not well developed. One major limitation that has blocked the progress, although mental disorders affect the brains, is the difficulty in accessing neuronal cells from patients. To overcome this dilemma, the program for which the PI serves as director, has systematically collected tissues and cells (lymphocytes, lymphoblasts, fibroblasts, induced pluripotent stem cells, and olfactory neurons via nasal biopsy) from patients with SZ as well as normal controls. Collection of blood cells is aimed to explore high throughput peripheral biomarkers. In our preliminary study, we observed excess levels of reactive oxygen species (ROS) in SZ lymphoblasts and olfactory neurons, compared with control cells. Interestingly, this difference between SZ and controls was accentuated following exposure of cells to increased glucose concentrations. Excess ROS in SZ was partially normalized by clozapine, which is utilized clinically in treatment of patients with SZ. Additional findings revealed redox imbalances in SZ cells. We conducted magnetic resonance spectroscopy of the individuals who provided tissue/cell samples and obtained preliminary data that suggest a decrease glutathione in the anterior cingulate cortex. On the basis of our preliminary data and previous studies by others, we hypothesize that cells derived from SZ patients may have intrinsic susceptibility that results in oxidative stress, which may be further represented under glucose overload. We hypothesize that this susceptibility is associated with SZ as a trait marker, being common in both neuronal and non-neuronal cells. In this proposal, we plan to address this cellular susceptibility in greater detail, by measuring the levels of ROS and protein oxidation as well as investigating possible cellular mechanisms underlying this susceptibility, such as the glutathione (GSH) cascade, NADPH oxidase, NAD/NADH, and mitochondrial functions. We will address whether neuroleptics may decrease excess ROS associated with this susceptibility. Then, in the final Aim, we will examine biochemical changes in brains of the same set of subjects from whom we obtain cells. We plan to examine the manner in which cellular changes and susceptibility observed in lymphoblasts and olfactory neurons are manifested in the brain. Evidence of oxidative stress in the pathology of SZ has been reported in the history of SZ research, which is now highlighted by reports that oxidative stress can elicit SZ-associated interneuron deficit, a key pathophysiology of this disorder. Thus, our study with human cells, especially neurons, may provide important information for SZ research.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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Johns Hopkins University
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Sumitomo, Akiko; Saka, Ayumi; Ueta, Keisho et al. (2018) Methylphenidate and Guanfacine Ameliorate ADHD-Like Phenotypes in Fez1-Deficient Mice. Mol Neuropsychiatry 3:223-233
Sedlak, Thomas W; Nucifora, Leslie G; Koga, Minori et al. (2018) Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study. Mol Neuropsychiatry 3:214-222
Sumitomo, Akiko; Yukitake, Hiroshi; Hirai, Kazuko et al. (2018) Ulk2 controls cortical excitatory-inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons. Hum Mol Genet 27:3165-3176
Endo, Ryo; Takashima, Noriko; Nekooki-Machida, Yoko et al. (2018) TAR DNA-Binding Protein 43 and Disrupted in Schizophrenia 1 Coaggregation Disrupts Dendritic Local Translation and Mental Function in Frontotemporal Lobar Degeneration. Biol Psychiatry 84:509-521
Posporelis, Sotirios; Coughlin, Jennifer M; Marsman, Anouk et al. (2018) Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study. Biol Psychiatry Cogn Neurosci Neuroimaging 3:248-254
Kano, Shin-Ichi; Hodgkinson, Colin A; Jones-Brando, Lorraine et al. (2018) Host-parasite interaction associated with major mental illness. Mol Psychiatry :
Sumitomo, Akiko; Horike, Kouta; Hirai, Kazuko et al. (2018) A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson's disease and schizophrenia. Sci Adv 4:eaar6637
Rubin, Leah H; Sacktor, Ned; Creighton, Jason et al. (2018) Microglial activation is inversely associated with cognition in individuals living with HIV on effective antiretroviral therapy. AIDS 32:1661-1667
Fukudome, Daisuke; Hayes, Lindsay N; Faust, Travis E et al. (2018) Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances. Schizophr Res :
Lavoie, Joëlle; Gassó Astorga, Patricia; Segal-Gavish, Hadar et al. (2017) The Olfactory Neural Epithelium As a Tool in Neuroscience. Trends Mol Med 23:100-103

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