Immune molecules and synaptic connectivity in maternal immune activation offspring and schizophrenia

点击翻译按钮获取中文摘要

SUMMARY: 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.