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.
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.
|Guo, Ziyuan; Zhang, Lei; Wu, Zheng et al. (2014) In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell 14:188-202|
|Wen, Zhexing; Nguyen, Ha Nam; Guo, Ziyuan et al. (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515:414-8|
|Sun, Chicheng; Zhang, Lei; Chen, Gong (2013) An unexpected role of neuroligin-2 in regulating KCC2 and GABA functional switch. Mol Brain 6:23|
|Tang, Xin; Zhou, Li; Wagner, Alecia M et al. (2013) Astroglial cells regulate the developmental timeline of human neurons differentiated from induced pluripotent stem cells. Stem Cell Res 11:743-57|
|Wu, Xia; Huang, Lanting; Wu, Zheng et al. (2013) Homeostatic competition between phasic and tonic inhibition. J Biol Chem 288:25053-65|
|Sun, Chicheng; Cheng, Min-Chih; Qin, Rosie et al. (2011) Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Hum Mol Genet 20:3042-51|