Neural-immune mechanisms and synaptic connectivity in psychiatric illness

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The pathophysiological processes underlying neuropsychiatric disorders have been unknown; as a result, these disorders have lacked innovative medical therapies with new mechanisms of action. We recently identified the alleles underlying the human genome's largest population-level influence on risk of schizophrenia – a series of structural alleles of the complement C4A and C4B genes, each of which appears to affect schizophrenia risk in proportion to the amount of C4A expression it generates in the brain. We also found that C4 shapes synaptic refinement in a mouse model of postnatal activity-dependent synapse elimination. These findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. The goal of the work we envision for a Conte Center is to develop our understanding of neural-immune interactions and synapses while also generating novel scientific resources that can be used to evaluate current and future hypotheses about schizophrenia-implicated genes, neural-immune interactions, and critical periods for synaptic refinement. Our proposed work arises from close, successful collaboration of scientists with expertise in genomics, immunology, and neuroscience. We aim to accomplish our Center's missions through scientific projects and cores. Project 1 will seek to understand how CNS cells regulate the expression of complement and reprogram gene expression as they traverse critical periods in the maturation of their circuits. Project 2 will create mice that carry human C4 genes and alleles; examining how human C4 allelic diversity and expression levels affect microglia-mediated synaptic pruning and other processes. Project 3 will reveal the functional consequences of complement-cascade dysregulation – both over- and under-pruning – on circuit function and behavior. A Computational and Statistical Analysis Core will contribute to research in all three projects by facilitating analyses of genome-wide expression data and genome sequence data. An administrative core will coordinate biweekly lab meetings and outward-facing activities, including an annual symposium on emerging research at the interface of neuroscience, immunology and genomics. We hope to advance the search for molecular understanding of schizophrenia while advancing the understanding of brain development, the interacting influences of genes and environment on brain and behavior, and possibly general principles that could be applicable to the mechanisms and pathways that go awry in other mental illnesses.