Individuals with schizophrenia have increased humoral immunity to infectious and food antigens. Increased complement activation and increased levels of circulating immune complexes (CIC) are found in individuals with this disease. The complement factor C1q that binds these complexes is also highly expressed at synaptic locations in the developing cortex. Project 6 will test the hypothesis that DISC1 mutant mice display increased C1q activation in the brain. Furthermore, we predict that early postnatal exposure to an environmental trigger such as Toxoplasma gondii infection will further exacerbate C1q activation in the brain of DISC1 mutant mice to contribute to GABA interneuron and spine density deficits in the developing frontal cortex. Extensive case-controlled collections of blood and CSF taken at various stages of disease in conjunction with matched post-mortem serum and frontal cortex samples will allow parallel studies of human samples with DISC1 mutant mice.
Specific Aim 1 will test the hypothesis that following penetration of a model antigen, casein, through the GI barrier, C1q-associated immune complexes are formed, leaving molecular signatures in human samples that are traceable from the periphery to the CNS.
Specific Aim 2 will evaluate the hypothesis that CIS-related activation of the complement system in the brain of DISC1 mutant mice will be exacerbated by early postnatal infection with Toxoplasma gondii, leading to abnormal development of GABA interneuron and dendritic spines in the frontal cortex.

Public Health Relevance

This study integrates clinical and basic science to determine how environmental triggers of the immune response are applicable to schizophrenia. Peripheral and CNS molecular signatures gleaned from human samples will be used to develop biomarkers, and DISC1 mutant mouse studies will allow testing of how the proposed gene-environmental model may impact CNS immune activation during development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH094268-03
Application #
8515812
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$148,628
Indirect Cost
$57,964
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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

Showing the most recent 10 out of 130 publications