Disrupted-in-Schizophrenia-1 (DISC1) and neuronal nitric oxide synthase (nNOS), genetic risk factors for schizophrenia (SZ), have key roles in neurodevelopment. The goal of project 4 is to examine the role for NudE-like 1 (NDEL1), a SZ-associated DISC1 interactor, in convergence of the nNOS and DISC1 pathways for the development of prefrontal cortex (PFC) and resultant behaviors, and to explore the implication of nNOS signaling in SZ. nNOS signaling regulates neuronal differentiation, such as dendritic development. As a result, nNOS knockout (KO) mice display diverse abnormal behaviors. However, PFC-associated behaviors in nNOS KO mice have not yet been studied, whereas PFC-associated cognitive deficits have been frequently reported in SZ. We have previously reported that DISC1-NDEL1 interaction regulates neurite outgrowth. Interestingly, NDEL1 activates Cdc42, a critical regulator for dendritic development. Given that nNOS, NDEL1, and DISC1 are highly expressed in the cortical plate in developing cerebral cortex, NDEL1 may function as a downstream effector of nNOS signaling, regulated by DISC1 for the critical period of dendritic development in the neonatal stage. Thus, we hypothesize that (1) nNOS and NDEL1 are anchored by DISC1 for S-nitrosylation of NDEL1, (2) S-nitrosylation of NDEL1 facilitates the release of NDEL1 from the protein complex with DISC1 for Cdc42 activation, and (3) this signaling is required for dendritic development and resultant behaviors. These hypotheses will be tested with an emphasis on the basic neuroscience with behavioral Core (Core B). We will use an inducible gene expression system via in utero electroporation, which manipulates NDEL1 function exclusively in post-migratory neurons. This innovative approach allows us to dissect the temporal requirement for the studies of other genetic risk factors in DISC1 pathways, such as DISC1 (project 1), PCMI and RPGRIPIL (project 2), and DPYSL2/CRMP2 (project 3), as well as explore the molecular pathology of gene-environment interactions in animal models relevant to SZ (project 5 and 6). The implication of nNOS signaling in SZ will be further explored by genetic analysis of our patient cohort and molecular profile of nNOS KO mice in collaboration with project 3 and Core A.

Public Health Relevance

Many genetic risk factors for schizophrenia may function in common molecular pathways, contributing to high brain functions. We will explore a role for NDEL1, a genetic risk factor for schizophrenia, in convergence of the nNOS and DISC1 pathways for dendritic development in the neonatal stage, which may be crucial for prfrontal cortex-associated behaviors.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Fukudome, Daisuke; Hayes, Lindsay N; Faust, Travis E et al. (2018) Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances. Schizophr Res :
Prandovszky, Emese; Li, Ye; Sabunciyan, Sarven et al. (2018) Toxoplasma gondii-Induced Long-Term Changes in the Upper Intestinal Microflora during the Chronic Stage of Infection. Scientifica (Cairo) 2018:2308619
Sumitomo, Akiko; Saka, Ayumi; Ueta, Keisho et al. (2018) Methylphenidate and Guanfacine Ameliorate ADHD-Like Phenotypes in Fez1-Deficient Mice. Mol Neuropsychiatry 3:223-233
Weber, Natalya S; Gressitt, Kristin L; Cowan, David N et al. (2018) Monocyte activation detected prior to a diagnosis of schizophrenia in the US Military New Onset Psychosis Project (MNOPP). Schizophr Res :
Torniainen-Holm, Minna; Suvisaari, Jaana; Lindgren, Maija et al. (2018) Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population: 11-year follow-up study. Brain Behav Immun 69:480-485
Li, Ye; Viscidi, Raphael P; Kannan, Geetha et al. (2018) Chronic Toxoplasma gondii Infection Induces Anti-N-Methyl-d-Aspartate Receptor Autoantibodies and Associated Behavioral Changes and Neuropathology. Infect Immun 86:
Lindgren, Maija; Torniainen-Holm, Minna; Härkänen, Tommi et al. (2018) The association between toxoplasma and the psychosis continuum in a general population setting. Schizophr Res 193:329-335
Sedlak, Thomas W; Nucifora, Leslie G; Koga, Minori et al. (2018) Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study. Mol Neuropsychiatry 3:214-222
McFarland, Ross; Wang, Zi Teng; Jouroukhin, Yan et al. (2018) AAH2 gene is not required for dopamine-dependent neurochemical and behavioral abnormalities produced by Toxoplasma infection in mouse. Behav Brain Res 347:193-200
Severance, Emily G; Yolken, Robert H (2018) Deciphering microbiome and neuroactive immune gene interactions in schizophrenia. Neurobiol Dis :

Showing the most recent 10 out of 190 publications