Project 1. Project 1. An investigation of oligodendroglia in schizophrenia. Demyelinating diseases have been known to be associated with behavioral changes. Recently, the expression levels of several myelin-related genes have been shown to be consistently decreased in postmortem schizophrenic brains compared to controls. Magnetic transfer imaging (MTI) has also shown consistent reduction in myelin content in schizophrenic brains. Diffusion tensor imaging (DTI), which measures the directionality of white matter tracts, has shown a decrease in anisotropy in the brains of schizophrenic patients, suggesting disruptions in white matter tract coherence and directionality in this disease. These data together make a strong case for oligodendrocyte dysfunction in schizophrenia. The anterior cingulate cortex plays a significant role in motivation, attention, and behavior and, as a component of the limbic system, in affect and memory. It has been clearly implicated in schizophrenia by studies of cytoarchitectural postmortem changes and functional imaging showing hypometabolism in this region in schizophrenia. In this project, we propose a quantitative analysis of possible relationships between oligodendrocytic pathology and abnormalities in cytoarchitecture in the cingulate cortex of postmortem brains from schizophrenic patients and neuropathologic and brain imaging analyses of relevant mice mutants such as the Quaking mouse, as well as genetically modified mice such as MAG, RPTPfi, CNPase, or MAGI knock-outs. Our analyses will use advanced microscopy quantitative approaches including the most rigorous stereologic methods for cell counting, estimators of spatial cellular distribution and cytoarchitectural boundaries, as well as single cell morphology by intracellular loading of fluorescent dyes or gene-gun-based DiOlistics techniques. We also are assessing progression of potential changes in white matter integrity using high field magnetic resonance microscopy in vivo at 9.4 T in the relevant mouse models. The combined analysis of human specimens and relevant mice models within the context of this program offers a superb opportunity to investigate myelin deficits that have a clinical impact and to determine the molecular, developmental, and morphologic characteristics of the neuronal circuits whose alteration is likely to underlie the pathogenesis and clinical manifestations of schizophrenia. the molecular, developmental, and morphologic characteristics of the neuronal circuits whose alteration is likely to underlie the pathogenesis and clinical manifestations of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH066392-09S1
Application #
8479520
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$74,421
Indirect Cost
$30,515
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Mueller, Toni M; Yates, Stefani D; Haroutunian, Vahram et al. (2016) Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia. Schizophr Res :
Lek, Monkol; Karczewski, Konrad J; Minikel, Eric V et al. (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285-91
Pinner, Anita L; Tucholski, Janusz; Haroutunian, Vahram et al. (2016) Decreased protein S-palmitoylation in dorsolateral prefrontal cortex in schizophrenia. Schizophr Res 177:78-87
Bhambhvani, Hriday P; Simmons, Micah; Haroutunian, Vahram et al. (2016) Decreased expression of cortactin in the schizophrenia brain. Neuroreport 27:145-50
Scott, Madeline R; Rubio, Maria D; Haroutunian, Vahram et al. (2016) Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia. Neuropsychopharmacology 41:896-905
Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K et al. (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci 19:1442-1453
Sullivan, Courtney R; Funk, Adam J; Shan, Dan et al. (2015) Decreased chloride channel expression in the dorsolateral prefrontal cortex in schizophrenia. PLoS One 10:e0123158
Mueller, T M; Remedies, C E; Haroutunian, V et al. (2015) Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain. Transl Psychiatry 5:e612
Roussos, Panos; Katsel, Pavel; Fam, Peter et al. (2015) The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia. Alzheimers Dement 11:1163-70
Hertzberg, L; Katsel, P; Roussos, P et al. (2015) Integration of gene expression and GWAS results supports involvement of calcium signaling in Schizophrenia. Schizophr Res 164:92-9

Showing the most recent 10 out of 127 publications