Our lab has a longstanding interest in the diverse biological functions of the classical complement cascade in immunity and autoimmune disease. More recently, this has led us to work on the brain, specifically on the role of immune molecules in early neural development and in promoting psychiatric disease.  Currently, we have focused on immune mechanisms underlying schizophrenia and Neuropsychiatric lupus.  The latter disease is the development of neuropsychiatric symptoms in lupus patients. Surprisingly, in both cases, we find evidence of overactivation of a process known as microglia-complement mediated synaptic pruning.  Recent findings have revealed that the complement system plays an important role in this process, which is essential for normal brain function.  In schizophrenia, a major risk factor is over expression of the complement protein C4A (Sekar et al Nature 2016). Therefore, one major goal for our lab is to understand why C4A and not a similar gene C4B confers this elevated risk and how overexpression of C4A affects brain development. To study this problem, we have developed transgenic mouse strains that express various levels of human C4A and C4B.  Study of the mice shows that over expression of C4A leads to “over pruning” in the mouse visual system.  Remarkably, increased expression of C4A (but not C4B) in the brain can also affect behavior such as social interaction and anxiety. In the neuropsychiatric lupus disease model, we are finding that inflammatory cytokines from the peripheral immune system can enter the brain and activate microglia and neurons leading to changes in behavior.  How these pathways target specific neural circuits is also an ongoing area of investigation.  A better understanding of how the peripheral immune system influences the brain should identify new therapeutic targets.