Disrupted-in-Schizophrenia 1 (DISC1) is a genetic risk factor for schizophrenia and related mental illnesses, however the synaptic functions of DISC1 in mature neurons are largely unknown. Emerging evidence suggests that alterations of synaptic transmission might be the core feature and fundamental pathology of schizophrenia, thus the goal of this project is to understand the role of DISC1 in regulating synaptic protein functions in prefrontal cortical (PFC) neurons. We hypothesize that DISC1 exerts an important impact on synaptic transmission and plasticity by regulating NMDAR and GABAAR channels, two key targets involved in cognitive and emotional processes, and the synaptic function of DISC1 is altered in schizophrenia.
Two specific aims will be addressed to examine the impact of DISC1 on the expression, trafficking and function of NMDARs and GABAARs in rat PFC neurons, using in vitro and in vivo knockdown of DISC1 or overexpression of full-length or C-terminal truncated DISC1. The potential mechanisms for DISC1 regulation of NMDARs and GABAARs will also be explored. Our results would not only reveal significant mechanistic insights into the synaptic functions of DISC1, but may also provide novel targets for more effective therapeutic strategies to treat mental disorders.

Public Health Relevance

This study aims to understand the role of DISC1, a genetic risk factor for schizophrenia and related mental illnesses, in regulating synaptic protein (NMDAR and GABAAR channels) functions in prefrontal cortical neurons. Our results would not only reveal significant mechanistic insights into the synaptic functions of DISC1, but may also provide novel targets for more effective therapeutic strategies to treat mental disorders.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH101690-02
Application #
8703804
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Asanuma, Chiiko
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Plattner, Florian; Hernández, Adan; Kistler, Tara M et al. (2014) Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron 81:1070-83
Yuen, Eunice Y; Qin, Luye; Wei, Jing et al. (2014) Synergistic regulation of glutamatergic transmission by serotonin and norepinephrine reuptake inhibitors in prefrontal cortical neurons. J Biol Chem 289:25177-85
Cheng, Jia; Xiong, Zhe; Duffney, Lara J et al. (2014) Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors. Biol Psychiatry 76:953-62
Wei, Jing; Graziane, Nicholas M; Wang, Haitao et al. (2014) Regulation of N-methyl-D-aspartate receptors by disrupted-in-schizophrenia-1. Biol Psychiatry 75:414-24
Duffney, Lara J; Wei, Jing; Cheng, Jia et al. (2013) Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. J Neurosci 33:15767-78