The signaling specification of the post synaptic membrane known as the post-synaptic density (PSD), is one of the most complex signaling machineries in the neuron. Many of the genes that have been implicated as risk factors for the psychiatric disorders are thought to affect PSD proteins. Yet with these genetic discoveries, there has been a gap in defining underlying biological mechanisms that contribute to dysfunction at the PSD in complex brain disorders. Our primary objectives are to determine how mutations associated to schizophrenia (SCZ), disrupts protein interaction networks (PINs) at the PSD, how risk factors are functionally organized in PINs and how they are regulated by synaptic activity. We will use mouse genetic models, including the protein kinase TNiK and a mutant -model of SHANK3 found in patients with SCZ, mass spectrometry analysis, biochemical assays, and computational approaches to explore not only the normal function of PSD PIN in responding to synaptic activity, but also translate the human genetic findings into knowledge of how the function of this network is affected by mutations associated with psychiatric disease.

Public Health Relevance

Psychiatric disorders such as schizophrenia, are highly prevalent, start early in life, damage the affected individuals? productivity, and cause a high burden to individuals, families and society. Despite the profoundly negative effects of these disorders on public health and society, progress in the discovery of new therapeutic targets and mechanisms has been slow. The proposed research will increase our understanding of the molecular changes occurring at the synapse, that are likely to be important in the development of schizophrenia, helping the possibility to bridge the gap between the discoveries of human genetics and essential synaptic pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH115005-01A1
Application #
9593439
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Driscoll, Jamie
Project Start
2018-06-01
Project End
2023-03-31
Budget Start
2018-06-01
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Psychiatry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089