Schizophrenia is believed to be a neurodevelopmental disorder with synaptic abnormalities. Deficits in dopaminergic and GABAergic synaptic transmission have been associated with schizophrenia. Our long-term goal is to investigate molecular and cellular mechanisms of neurological disorders and identify novel drug target for therapeutic treatment. This proposal will study the function of neuroligin-2 (NL-2) mutations identified from schizophrenia patients. NL-2 is a cell adhesion molecule, localized specifically at inhibitory synaptic sites. Our own studies, together with others, demonstrate that NL-2 plays a critical role in promoting GABAergic synaptogenesis. Previous work had identified mutations of neuroligin-3 and neuroligin-4 in autism patients. Here, we report the identification of 4 NL-2 mutations (644A, 1528A, 1862A, and 1909A) from 400 schizophrenia patients, but none from 400 healthy controls, by our collaborators Dr. Chia-Hsiang Chen and colleagues. We performed functional analysis on one NL-2 mutant 644A using our molecularly engineered GABAergic synapse system, and discovered strong defect in promoting GABAergic synapse formation. Based on this exciting finding, this proposal will: 1) Further investigate the functional consequences of all 4 NL-2 mutations on GABAergic synapse formation in heterologous synapse system, as well as in cortical neurons;2) Establish a novel transgenic mouse model for schizophrenia and related neurodevelopmental disorders. Completion of this proposal will unveil a novel link between NL-2 mutations and schizophrenia, and provide a potential transgenic animal model for studying mental disorders.

Public Health Relevance

Schizophrenia is a devastating mental illness afflicting about 1 percent of world populations. We report the identification of 4 neuroligin-2 mutations from schizophrenia patients, and pilot studies on one such mutant (644A) revealed functional deficit in promoting GABAergic synapse formation. This proposal will investigate the functional relationship between neuroligin-2 mutations and schizophrenia, and provide a novel transgenic mouse model for further studying schizophrenia and related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH092740-02
Application #
8196948
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
2010-12-01
Project End
2013-03-31
Budget Start
2011-12-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$182,674
Indirect Cost
$57,674
Name
Pennsylvania State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
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