PROJECT 1 Despite its prevalence and enormous cost to society, current treatments for schizophrenia (SZ) are not effective in all individuals and do little to treat the disabling cognitive and negative symptoms. Thus, there is a pressing need to identify new molecular pathways to target in developing new compounds and tools for earlier diagnosis and treatment of SZ. Our Center is focused on testing the hypothesis that immune molecules may constitute such a target pathway. Immune genes located within the major histocompatibility complex (MHC) have been reliability identified in recent genome-wide association studies, while maternal infections are among the best-established environmental risk factors for the illness. The development of mouse and non-human primate (NHP) models of maternal infection has also strengthened the link between maternal immune activation (MIA) and SZ because these models recapitulate many SZ related phenotypes at both the neurobiological and behavioral levels. Although our work is providing increasingly compelling validation for their efficacy in mimicking core phenotypes of SZ, little is known about how MIA alters brain development after birth to cause SZ-related phenotypes in offspring. This project will determine how and when MIA alters neural connectivity during postnatal development and whether those changes depend on MIA-induced changes in MHCI levels in the brains of offspring. To accomplish these objectives, this project will undertake three specific aims to determine: 1) if MIA alters synapse density and type in the brains of offspring of the mouse and NHP models throughout postnatal development and in postmortem brain tissue from individuals with SZ using approaches that include an innovative technique called array tomography; 2) if MIA alters microglial activation and levels of immune molecules, including MHCI, in the brains of offspring in both animal models throughout development as well as in postmortem brain tissue from individuals with SZ; 3) if changes in immune molecules in the brains of offspring from the mouse model mediate the effects of MIA by assessing whether restoring levels of neuronal MHCI back to normal prevents MIA-induced changes in synaptic connectivity and SZ-like behaviors in offspring. By accomplishing these aims, Project 1 will directly address the central hypothesis of the Center in a mechanistic manner. Moreover, performing these experiments across scales will identify which MIA-induced changes in synaptic connectivity are relevant to human disease through their conservation in the NHP model. Results from this project are essential to the success of the other projects in the Center in providing a phenotypic read-out for changes in transcriptional networks (Project 2) and in structural and functional connectivity (Project 3), as well as critical information about whether microglial activation mediates changes in neural inflammation (Project 4) in MIA models and humans with SZ.If successful, results from this project will identify novel targets for developing more effective diagnostic tools and therapies for SZ and other psychiatric illnesses with a neural-immune basis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH106438-01
Application #
8855881
Study Section
Special Emphasis Panel (ZMH1-ERB-L (01))
Project Start
Project End
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$329,369
Indirect Cost
$113,764
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Gandal, Michael J; Zhang, Pan; Hadjimichael, Evi et al. (2018) Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362:
Maddock, Richard J; Caton, Michael D; Ragland, J Daniel (2018) Estimating glutamate and Glx from GABA-optimized MEGA-PRESS: Off-resonance but not difference spectra values correspond to PRESS values. Psychiatry Res Neuroimaging 279:22-30
Gandal, Michael J; Haney, Jillian R; Parikshak, Neelroop N et al. (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359:693-697
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Careaga, Milo; Murai, Takeshi; Bauman, Melissa D (2017) Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol Psychiatry 81:391-401
McAllister, A Kimberley (2017) Immune Contributions to Cause and Effect in Autism Spectrum Disorder. Biol Psychiatry 81:380-382
Gandal, Michael J; Leppa, Virpi; Won, Hyejung et al. (2016) The road to precision psychiatry: translating genetics into disease mechanisms. Nat Neurosci 19:1397-1407
Estes, Myka L; McAllister, A Kimberley (2016) Maternal immune activation: Implications for neuropsychiatric disorders. Science 353:772-7
Estes, Myka L; McAllister, A Kimberley (2016) IMMUNOLOGY. Maternal TH17 cells take a toll on baby's brain. Science 351:919-20
Gandal, Michael J; Geschwind, Daniel H (2016) The Genetics-Driven Revival in Neuropsychiatric Drug Development. Biol Psychiatry 79:628-30

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