This project is dedicated to the development and characterization of mouse model systems that best reflectthe 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 ofOMR 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 inschizophrenia will then be assessed for behavioral deficits. The behavioral phenotyping test battery willinclude 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 withthese purely behavioral tests will be pharmacological probes to ascertain whether pharmacological profilescommonly viewed as prototypical for rodent models of schizophrenia are also evidenced by the OMR genedeficient mice. Once 'best-fit' model systems have been identified, they will be studied longitudinally toascertain the evolution of gene expression and behavioral deficits from 3 months of age through to 18months of age. In addition, laser capture microdissection techniques will be employed to investigate geneexpression in identified cell groups. In collaboration with Project 1, the 'best-fit' mouse model system will besystematically imaged by DTI in vivo at ages corresponding to those for behavioral testing. In collaborationwith Project 3, brain tissue specimens from additional mice will be studied for changes in oligodendroglialproliferation, differentiation and survival. Significant progress has already been made in this regard. All ofthe behavioral test paradigms have been piloted and parameters have been optimized for use in mice in ourphenotyping facility (results and descriptions appended). Three of the 4 animal model systems proposed foruse (Quaking, Olig2, and MAG) have been obtained. Some studies have already been completed in thesemice and colonies have been established to enable more large scale studies.
Showing the most recent 10 out of 153 publications
