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
Jasinska, Anna J; Zelaya, Ivette; Service, Susan K et al. (2017) Genetic variation and gene expression across multiple tissues and developmental stages in a nonhuman primate. Nat Genet 49:1714-1721
Mitelman, Serge A; Bralet, Marie-Cecile; Mehmet Haznedar, M et al. (2017) Positron emission tomography assessment of cerebral glucose metabolic rates in autism spectrum disorder and schizophrenia. Brain Imaging Behav :
Mueller, Toni M; Yates, Stefani D; Haroutunian, Vahram et al. (2017) Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia. Schizophr Res 182:66-73
Mancuso, Nicholas; Shi, Huwenbo; Goddard, Pagé et al. (2017) Integrating Gene Expression with Summary Association Statistics to Identify Genes Associated with 30 Complex Traits. Am J Hum Genet 100:473-487
Zhu, Lingxue; Lei, Jing; Devlin, Bernie et al. (2017) TESTING HIGH-DIMENSIONAL COVARIANCE MATRICES, WITH APPLICATION TO DETECTING SCHIZOPHRENIA RISK GENES. Ann Appl Stat 11:1810-1831
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
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
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
Li, Ming; Jaffe, Andrew E; Straub, Richard E et al. (2016) A human-specific AS3MT isoform and BORCS7 are molecular risk factors in the 10q24.32 schizophrenia-associated locus. Nat Med 22:649-56
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

Showing the most recent 10 out of 134 publications