Schizophrenia and bipolar I disorder are serious psychiatric illnesses that affect approximately 4% of the Australian population. Both illnesses are thought to occur in individuals with a genetic predisposition after they encounter as yet unknown detrimental environmental factors. Postmortem central nervous system (CNS) studies have been undertaken to identify the combined impact of these two factors on both cellular and molecular cytoarchitecture. In particular, studies from our laboratories have shown changed levels of the glial-derived proteins apolipoprotein E and D in the cortex of subjects with schizophrenia and bipolar I disorder. In addition, we have shown changes in levels of S100β, in the dorsolateral prefrontal cortex from subjects with bipolar II disorder. Significantly, it is known that levels of S100β are known to be potently regulated by serotonin through the serotonin1A receptor and receptors for apolipoprotein E are localized on neurons. Our data would therefore support the hypothesis that at least part of the pathology of schizophrenia and bipolar disorder are because of a breakdown in communication between neurons and glia, which occurs most potently at the tripartite synapse. Our published data and recent data from our microarray study have now shown that there is a decrease in the expression of specific apolipoprotein E receptors in the CNS of subjects with schizophrenia, further supporting our hypotheses of altered neuronal glia communication in psychiatric disease and will be summarized in this presentation.