This project is dedicated to the development and characterization of mouse model systems that best reflect the myelin and oligodendrocyte related (OMR) gene expression deficits in persons with schizophrenia. Several different genetically modified mouse model systems will be evaluated (e.g., Quaking, MAG, PTPRZ1, and Olig2. Each of these mouse model systems will be screened for deficits in the expression of OMR genes using a panel of OMR genes that we have shown to be differentially affected in schizophrenia. Those that evidence gene expression deficits on at least 3 OMR genes known to be affected in schizophrenia will then be assessed for behavioral deficits. The behavioral phenotyping test battery will include screening tests of simple (e.g., reflexes, locomotion, balance, sensation) as well as complex (learning, memory, startle, prepulse inhibition of startle, social interaction, anxiety) behaviors. Coupled with these purely behavioral tests will be pharmacological probes to ascertain whether pharmacological profiles commonly viewed as prototypical for rodent models of schizophrenia are also evidenced by the OMR gene deficient mice. Once """"""""best-fit"""""""" model systems have been identified, they will be studied longitudinally to ascertain the evolution of gene expression and behavioral deficits from 3 months of age through to 18 months of age. In addition, laser capture microdissection techniques will be employed to investigate gene expression in identified cell groups. In collaboration with Project 1, the """"""""best-fit"""""""" mouse model system will be systematically imaged by DTI in vivo at ages corresponding to those for behavioral testing. In collaboration with Project 3, brain tissue specimens from additional mice will be studied for changes in oligodendroglial proliferation, differentiation and survival. Significant progress has already been made in this regard. All of the behavioral test paradigms have been piloted and parameters have been optimized for use in mice in our phenotyping facility (results and descriptions appended). Three of the 4 animal model systems proposed for use (Quaking, Olig2, and MAG) have been obtained. Some studies have already been completed in these mice and colonies have been established to enable more large scale studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH066392-09S1
Application #
8479524
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

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