Schizophrenia is a disorder of neuronal connectivity, at least in part, with developmental origin. Functional disturbance of the cerebral cortex, especially the prefrontal cortex, has been reproducibly reported. Recent genetic studies have suggested that some of the genetic susceptibility factors may have a role in formation of synapses. These factors include Disrupted-ln-Schizophrenia (DISC1), neuronal nitric oxide synthase (nNOS), CAPON, NDEL1, and ErbB4. DISC1 interacts with several intracellular proteins, including Kalirin and other susceptibility factors for the disease, as an adaptor protein in the postsynaptic density. Thus, we will study a role for molecular pathway(s) involving DISC1 in synaptic spine formation in the developing cerebral cortex. In the first half of this project (Aims 1 and 2), we will use primary cortical neurons to elucidate molecular pathways of DISC1/ Kalirin-7 and DISC1/nNOS/NDEL1 for proper spine formation in pyramidal neurons, possibly by influencing Rho-like small G-proteins, especially Rac1. We hypothesize that DISC1 regulates access of Kalirin-7 and NDEL1 to Rac1 and related proteins, in response to the activation of the NMDA glutamate receptor, and regulates synaptic spine formation in a proper manner. In the second half of this project (Aim 3), we will test how disturbance of DISC1 and its interaction with Kalirin-7 and other synaptic proteins lead to morphological changes of the spines in vivo and result in behavioral alterations, which will be studied in collaboration with Core B. Key mediators studied in this project, including Kalirin-7 and Rac1, will be evaluated by genetic analysis in Core C. Taken together, we hope to clarify how convergence of twto critical factors for schizophrenia, such as glutamate and DISC1, occurs at postsynaptic sites. We wish to elucidate mechanisms whereby this disease pathway, involving DISC1 and its interactors, leads to deficits in the synaptic spines in the pyramidal neurons of the frontal cortex and resultant behavioral abnormalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory Grants (P20)
Project #
5P20MH084018-03
Application #
8080397
Study Section
Special Emphasis Panel (ZMH1)
Project Start
2010-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$216,792
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Pandey, Himani; Bourahmoune, Katia; Honda, Takato et al. (2017) Genetic interaction of DISC1 and Neurexin in the development of fruit fly glutamatergic synapses. NPJ Schizophr 3:39
Lavoie, Joëlle; Sawa, Akira; Ishizuka, Koko (2017) Application of olfactory tissue and its neural progenitors to schizophrenia and psychiatric research. Curr Opin Psychiatry 30:176-183
Lavoie, Joëlle; Gassó Astorga, Patricia; Segal-Gavish, Hadar et al. (2017) The Olfactory Neural Epithelium As a Tool in Neuroscience. Trends Mol Med 23:100-103
Cash-Padgett, Tyler; Sawa, Akira; Jaaro-Peled, Hanna (2016) Increased stereotypy in conditional Cxcr4 knockout mice. Neurosci Res 105:75-9

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