Disturbance in brain development during adolescence may underlie schizophrenia (SZ). Although many reports showed that astrogliosis is not observed in SZ, accumulating evidence suggests that altered function of astrocytes and microglia as well as aberrant immune/inflammatory responses may also underlie SZ. Nonetheless, it is unclear whether or to what extent glial cells and inflammation are involved in altered brain development during adolescence. Recently, we have found that the expression of immune/stress related genes is altered in live neuronal cells derived from SZ patients. The most affected genes include glutathione S-transferase theta 2 (GSTT2) gene, which regulates cellular detoxification system and protects cells from reactive oxygen metabolites. Oxidative stress activates innate immune signaling and contributes to inflammation in various diseases such as diabetes, atherosclerosis, and neurodegenerative disorders. Indeed, we observed increased expression of proinflammatory cytokines by oxidative stress. In the proposed study, we will test the hypothesis that glial cell activation and inflammatory responses during adolescence contribute to altered development of glutamatergic synapses. We will perform in vivo knockdown of GSTT2 expression at specific developmental stages in mice as a model to induce glial cell activation and inflammation via increased oxidative stress. We will characterize the effects of knockdown on the activation of microglia and astrocytes as well as the production of proinflammatory cytokines. We will also assess the effects of knockdown on development of glutamatergic synapses and the expression of synaptic/dendritic immune molecules. Finally, we will address the role of innate immune signaling in microglia by using microglia-specific deletion of MyD88, a molecule that plays a central role in innate immune signaling. The training and research proposal will enable the candidate to develop into an independent investigator in neuropsychiatry research. The project will contribute to the understanding of the roles for glial cells and inflammation in altered brain development during adolescence relevant to SZ.

Public Health Relevance

Although glial cell dysfunction and altered immune/inflammatory status have been suggested in patients with schizophrenia (SZ), it is not clear how they contribute to the pathology of SZ. In this study, we will characterize the role of glial cell activation and inflammatory response in altered brain maturation during adolescence. By utilizing our recent findings that SZ neurons have intrinsic susceptibility to oxidative stress, we will provide a model mechanism how SZ-associated neuronal defects lead to altered development of glutamatergic synapses via glia-mediated inflammatory responses. The study will contribute to the further understanding of altered development of glutamatergic synapses as well as identification of novel therapeutic target(s) that enables early intervention treatment for SZ.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Transition Award (R00)
Project #
4R00MH093458-03
Application #
8836668
Study Section
Special Emphasis Panel (NSS)
Program Officer
Desmond, Nancy L
Project Start
2011-08-22
Project End
2017-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$249,000
Indirect Cost
$91,852
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218