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.
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).
|Tanaka, Motomasa; Ishizuka, Koko; Nekooki-Machida, Yoko et al. (2017) Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease. J Clin Invest 127:1438-1450|
|Koh, Ming Teng; Shao, Yi; Rosenzweig-Lipson, Sharon et al. (2017) Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia. Schizophr Res :|
|Dickerson, Faith; Severance, Emily; Yolken, Robert (2017) The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun 62:46-52|
|Nucifora Jr, Frederick C; Mihaljevic, Marina; Lee, Brian J et al. (2017) Clozapine as a Model for Antipsychotic Development. Neurotherapeutics 14:750-761|
|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|
|Yoshimura, Atsushi; Goodson, Carrie; Johns, Jordan T et al. (2017) Altered cortical brain activity in end stage liver disease assessed by multi-channel near-infrared spectroscopy: Associations with delirium. Sci Rep 7:9258|
|Suvisaari, Jaana; Torniainen-Holm, Minna; Lindgren, Maija et al. (2017) Toxoplasma gondii infection and common mental disorders in the Finnish general population. J Affect Disord 223:20-25|
|Sagata, Noriaki; Kato, Takahiro A; Kano, Shin-Ichi et al. (2017) Dysregulated gene expressions of MEX3D, FOS and BCL2 in human induced-neuronal (iN) cells from NF1 patients: a pilot study. Sci Rep 7:13905|
|Nishi, Akira; Numata, Shusuke; Tajima, Atsushi et al. (2017) De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity. Sci Rep 7:2887|
|Namkung, Ho; Kim, Sun-Hong; Sawa, Akira (2017) The Insula: An Underestimated Brain Area in Clinical Neuroscience, Psychiatry, and Neurology. Trends Neurosci 40:200-207|
Showing the most recent 10 out of 164 publications