Why It Is Important

Schizophrenia (SZ) is a major mental disorder that affects 1% of the population worldwide. Although the cause of SZ is not known, there is growing support for the idea that it is a neurodevelopmental disorder resulting from disruption of the wiring of cortical circuits. A wide range of genes and environmental factors have been linked to SZ and many of these factors unexpectedly alter immune function. Individuals with SZ display abnormal levels of immune signaling proteins called cytokines in their brains and genes encoding immune proteins, including cytokines and their receptors and major histo-compatibility complex molecules (MHC), are correlated with increased susceptibility for SZ. In addition, maternal infection during early to mid-gestation is the most compelling environmental risk factor for SZ. These discoveries are significant because recent advances in developmental neurobiology point to a key role for immune molecules in brain development and function. The primary goal of our collaborative project is to test the hypothesis that dysregulation of immune signaling molecules in the brain leads to altered neural circuitry and function, which cause the aberrant behaviors characteristic of SZ. If so, then we will target these immune signaling pathways for development of novel diagnostic tools and therapeutics with the ultimate goal of discovering new treatments for SZ.

Our Approach

This I-CAN-SZ initiative brings together a collaborative, interdisciplinary group of scientists to definitively test the hypothesis that immune dysregulation contributes to the development of SZ by altering brain cytokine and MHCI signaling. We are also developing novel tools to non-invasively image abnormal immune activation in the brain for diagnostic and drug discovery purposes. This high risk, high yield multidisciplinary effort to validate an immunological, developmental model of SZ is based on an unprecedented approach involving coordinated experiments by 5 accomplished research groups with appointments in the UC Davis School of Medicine, the College of Biological Sciences, the College of Letters and Sciences, and the School of Engineering. This will be the first study to characterize changes in peripheral immune activation, neural inflammation, cortical anatomy, and behaviors simultaneously in high-risk individuals during their first-break for SZ and mouse and non-human primate (NHP) immune-based model systems.

Impacts & Highlights

• Discovery of the hallmark of psychosis and SZ—enhanced uptake of dopamine in the striatum—in the brains of non-human primate (NHP) maternal immune activation (MIA) offspring. This result is highly significant because it unequivocally validates our animal models as relevant for SZ.
• Discovering a set of cytokine receptors whose expression is altered in MIA offspring across such disparate species ad mice and non-human primates. Cytokine receptor expression is altered in the brains of both mouse and NHP MIA offspring, relative to controls. Remarkably, 5 cytokines (out of 23 tested) were decreased in the NHP brain and all of these overlap (in kind or in function) with those identified in the mouse MIA brains. This discovery indicates that these cytokine receptors may be part of a central molecular pathway that underlies the SZ-like neuroanatomical and behavioral abnormalities in offspring. Because the same receptors are altered in the brains of such disparate species, it is likely that the receptors we have identified will also be altered in human disease. This discovery was the basis for our provisional patent, submitted in May 2014.
• The results from the I-CAN-SZ RISE team provided the knowledge for the basis of an application to NIMH for a Silvio O. Conte Center, which was funded and started on April 1, 2015
• The Center is now well established and the new research projects are proceeding

Team Faculty

Kimberley McAllister	Professor of Neurology and Neurobiology, Physiology & Behavior
Cameron Carter	Professor of Psychiatry & Behavioral Sciences
David Amaral	Professor of Psychiatry & Behavioral Sciences
Melissa Bauman	Associate Professor of Psychiatry & Behavioral Sciences
Paul Ashwood	Assistant Professor of Medical Microbiology & Immunology
Judy Van de Water	Professor of Internal Medicine
Julie Sutcliffe	Associate Professor of Internal Medicine
Simon Cherry	Professor of Biomedical Engineering, and Director of The Center for Molecular & Genomic Imaging
Doug Rowland	Project Scientist for The Center for Molecular & Genomic Imaging
Deb Van Der List	Staff Research Associate for The Center for Neuroscience
Tyler Lesh	Assistant Project Scientist of Psychiatry & Behavioral Sciences
Ruth Weir	Postdoc of Psychiatry & Behavioral Sciences
Myka Estes	Postdoc of Neuroscience
Reihaneh Forghany	Graduate Student of Internal Medicine
Lindsay Wessel	Graduate Student of Psychiatry & Behavioral Sciences
Ali Izadi	Graduate Student of Neurological Surgery
Vivian Trinh	Undergraduate Student of Neurobiology, Physiology & Behavior
Ryan Philips	Graduate Student of Neuroscience
Mario Parks	Graduate Student of Neuroscience
Destanie Cummings	Graduate Student of Neurobiology, Physiology & Behavior

For more information on this program, please contact Christine Parks [email protected].