Lithium is the first line of therapy in the treatment of bipolar disorder yet its mechanism of action remains unclear. The goal of this project is to apply basic research methods to the study of mental health in order to identify the molecular targets of lithium in the treatment of bipolar disorder. Previous work in this laboratory has shown that lithium inhibits the signaling molecule Glycogen Synthase Kinase-313 (GSK-3B) and activates the Wnt/l3-catenin signaling pathway, providing an explanation for the effects of lithium on the development of diverse organisms. Several laboratories have also shown that lithium inhibits GSK-3B in cultured neurons and in whole animals; however, GSK-3B still has not been demonstrated to be the relevant target of lithium in the treatment of neuropsychiatric disorders. Work supported by this ROl has led to the identification of a novel peptide inhibitor of GSK-3B derived from the GSK-3 jnteraction domain (GID) of axin. This peptide inhibits the enzymatic activity of GSK-313 in vivo and leads to strong activation of the Wnt signaling pathway, mimicking the activity of lithium. This peptide thus provides an alternative to lithium that can be used to test the hypothesis that inhibition of GSK-313 is important in the response to lithium in non-developmental settings, particularly in behavior. In the continuation of this project, the features of the GID peptide required for inhibition of GSK-3B will be further defined and the mechanism of inhibition will be characterized. Transgenic mice expressing the GID peptide, as well as downstream activators and inhibitors of Wnt signaling, will be generated using a neuron specific, postnatal promoter. These transgenic mice will be assessed in lithium-sensitive behavioral assays to test whether they either mimic (GID or Wnt activators) or block (antagonists of Wnt signaling) the behavioral effects of lithium. In addition, transgenic reporter mice will be generated to provide an in vivo read-out for activation of the wnt pathway in the brain. These reporter lines may allow localization of lithium sensitive regions in the mammalian brain. This approach may allow the development of new and safer therapeutic agents for the treatment of bipolar disorder and should also help to elucidate the neuronal signaling pathways involved in the pathogenesis of this common and debilitating disorder.
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