Adult brain function and behavior are influenced by neuronal network formation during development. Consequently, disturbances of brain development may underlie the pathology of adult mental disorders, such as schizophrenia (SZ) and mood disorders. Consistent with this notion, genetic susceptibility factors for these disorders that have been recently indentified, including Disrupted-in-Schizophrenia-1 (DISC1) and PCM1, have roles during neurodevelopment and are likely to cooperate, forming molecular """"""""pathways."""""""" Meanwhile, epidemiological studies have indicated that many environmental factors contribute to schizophrenia during neurodevelopment. P50 Schizophrenia Research Center at Johns Hopkins, therefore, is to address the key question of how defects of cortical development elicited by combinations of genetic and environmental risk factors lead to molecular, histological, and behavioral deficits associated with the frontal cortex in adulthood, which are relevant to SZ. Based on our preliminary studies, we hypothesize that DISC1 and its interactors are useful genetic probes for this study. Accordingly, the four major aims of this entire center are as follows: 1) to clarify the mechanisms whereby several different combinations of DISC1 and interactors (e.g., Karilin-7, PCM1, RPGRIP1L, CRMP2, nNOS, and NDEL1) mediate distinct processes during neurodevelopment, which in turn affect postnatal brain maturation and result in deficits of the frontal cortex and behavioral abnormalities relevant to SZ;2) to determine how environmental factors relevant to SZ (prenatal immune activation, postnatal activation of complement cascade, and postnatal infection of Toxoplasma Gondii) influence genetic vulnerability associated with DISCI, which eventually contribute to the deficits of the frontal cortex and behavioral abnormalities relevant to SZ;3) to identify molecular targets for possible biomarkers of SZ and SZ-associated endophenotypes by comparing altered expression profiles in preclinical models and human tissues;4) to identify rare genetic variants associated with SZ and/or some endophenotypes associated with SZ by pinpointing novel candidates for genetic sequencing from biological studies. In this center, 6 projects and 2 cores will collaborate to achieve these scientific goals.

Public Health Relevance

This multifaceted proposal systematically arranged by experts of many different areas is expected to address neurodevelopmental cascades for schizophrenia elicited by genetic and environmental risk factors of the disorder. The findings are expected to be an important basis for early identification for patients, novel biomarkers, and novel therapeutic strategies for the disease (especially its early intervention).

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Study Section
Special Emphasis Panel (ZMH1)
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Zalcman, Steven J
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Johns Hopkins University
Schools of Medicine
United States
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Severance, Emily G; Gressitt, Kristin L; Stallings, Cassie R et al. (2016) Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study. Brain Behav Immun :
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48
Severance, Emily G; Gressitt, Kristin L; Stallings, Catherine R et al. (2016) Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. NPJ Schizophr 2:16018
Severance, Emily G; Yolken, Robert H; Eaton, William W (2016) Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res 176:23-35
Saito, A; Taniguchi, Y; Rannals, M D et al. (2016) Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1. Mol Psychiatry 21:1449-59
Katsanis, Nicholas (2016) The continuum of causality in human genetic disorders. Genome Biol 17:233
Tankou, Stephanie; Ishii, Kazuhiro; Elliott, Christina et al. (2016) SUMOylation of DISC1: a potential role in neural progenitor proliferation in the developing cortex. Mol Neuropsychiatry 2:20-27
Macpherson, Tom; Morita, Makiko; Wang, Yanyan et al. (2016) Nucleus accumbens dopamine D2-receptor expressing neurons control behavioral flexibility in a place discrimination task in the IntelliCage. Learn Mem 23:359-64
Koh, Ming Teng; Shao, Yi; Sherwood, Andrew et al. (2016) Impaired hippocampal-dependent memory and reduced parvalbumin-positive interneurons in a ketamine mouse model of schizophrenia. Schizophr Res 171:187-94
Owen, Michael J; Sawa, Akira; Mortensen, Preben B (2016) Schizophrenia. Lancet 388:86-97

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