Schizophrenia (SZ) is believed to be a disorder of neural connectivity involving the prefrontal cortex. Several lines of evidence have suggested that abnormal synaptic reorganization, such as synaptic pruning, may underlie the pathology of SZ. We previously reported the localization of DISCI, a major risk factor of SZ, in the postsynaptic density in mature neurons. We then demonstrated that DISCI is required for proper maintenance of the synapse and spine by functionally linking to activation of NMDA-type glutamate receptor and conveying the signal to Kalirin-7 (Kal-7) and Rac1. Consistently, several groups, including ours, have obtained preliminary results that DISC1 mutant animal models show a decrease in the spine density in the cortex in adulthood. Considering a peak of DISC1 expression observed in early adolescence and importance of synaptic pruning possibly in the pathology of SZ, we now hypothesize that the DISC1-Kal-7- Rac1 cascade may, at least in part, play a role in the pathology of SZ, especially during the prodromal stage of the disorder in adolescence. We will have four aims as follows: (1) to examine synaptic disturbances in the cortex in several DISC1 mutant animal models in the developmental course from early adolescence to adulthood;(2) to identify whether the deficits of the pyramidal neurons, especially those associated with the spine, primarily lead to circuitry deficits of the frontal cortex and behavioral deficits relevant to SZ;(3) to test whether modulation of PAK1 (a key downstream mediator of Rac1) protects against DISC1-elicited synapse deterioration;and (4) to examine molecular profiles in the frontal cortex of DISC1 mutant animal models, especially those in the pyramidal neuron layers. Through these studies, we wish to characterize SZ-relevant synapse pathology in DISC1 animal models, identify mechanisms of how synaptic disturbance can lead to circuitry defects and behavioral abnormalities, pin down a way of intervention against the synapse pathology (towards therapeutic strategies), and establish changes in the molecular signature associated with the synaptic changes towards biomarker identification.

Public Health Relevance

Synaptic pathology is expected to underlie behavioral deficits relevant to schizophrenia. Many developmental defects elicited by the DISC1 interactome studied in other projects may result in this synaptic change as a final common pathway towards the disease in adulthood. Thus detailed characterization of synapse pathology has a particular significance in the systematic study of schizophrenia in the center.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH094268-04
Application #
8681532
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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 :
Sumitomo, Akiko; Yukitake, Hiroshi; Hirai, Kazuko et al. (2018) Ulk2 controls cortical excitatory-inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons. Hum Mol Genet 27:3165-3176
Endo, Ryo; Takashima, Noriko; Nekooki-Machida, Yoko et al. (2018) TAR DNA-Binding Protein 43 and Disrupted in Schizophrenia 1 Coaggregation Disrupts Dendritic Local Translation and Mental Function in Frontotemporal Lobar Degeneration. Biol Psychiatry 84:509-521
Koh, Ming Teng; Ahrens, Paige S; Gallagher, Michela (2018) A greater tendency for representation mediated learning in a ketamine mouse model of schizophrenia. Behav Neurosci 132:106-113
Gusev, Alexander; Mancuso, Nicholas; Won, Hyejung et al. (2018) Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet 50:538-548
Koh, Ming Teng; Shao, Yi; Rosenzweig-Lipson, Sharon et al. (2018) Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia. Schizophr Res 193:119-125
Nucifora Jr, Frederick C; Woznica, Edgar; Lee, Brian J et al. (2018) Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol Dis :
Xu, Zhexue; Zhang, Shu; Huang, Liyuan et al. (2018) Altered Resting-State Brain Activities in Drug-Naïve Major Depressive Disorder Assessed by fMRI: Associations With Somatic Symptoms Defined by Yin-Yang Theory of the Traditional Chinese Medicine. Front Psychiatry 9:195

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