The long-term goal of this project is to identify cellular mechanisms of action of lithium and other mood stabilizers in order to contribute to understanding the underlying pathophysiology and to enhance treatment of mood disorders. To achieve this, four specific aims are to be addressed. 1. Lithium is a direct inhibitor of glycogen synthase kinase-3 (GSK3), and recently we showed this action is amplified in vivo in mouse brain by phosphorylation of select pools of GSK3, substantially increasing the inhibitory effect of a therapeutic level of lithium.
Specific Aim 1 will examine this amplification mechanism inhibiting the activity of GSK3, the influence of lithium, and this mechanism will be examined in Aims 2-4. 2. We recently discovered that serotonergic activity inhibits GSK3 in mouse brain in vivo, revealing a direct link between serotonergic activity and lithium's target.
Specific Aim 2 will examine the in vivo mechanisms by which serotonergic activity regulates GSK3, the serotonin receptor subtypes that are involved, the effects of mood stabilizers and antidepressants, and signaling pathways involved. 3. The goal of the third aim is to establish an in vivo model of pathological activation of GSK3 that is counteracted by mood stabilizers and antidepressants. We will follow-up our recent findings that In mouse brain in vivo hypoxia rapidly and robustly activates GSK3 and this is blocked by in vivo administration of mood stabilizers or imipramine.
Specific Aim 3 will test the hypothesis that hypoxia activates GSK3 and mood stabilizers and antidepressants attenuate this GSK3 activation and will investigate mechanisms underlying these interactions in cultured cells, since this provides the only model of pathophysiological GSK3 activation in vivo that is attenuated by these therapeutic agents. 4. Substantial evidence indicates that neurogenesis may be impaired in mood disorders and be promoted by therapeutic agents.
Specific Aim 4 will test the hypothesis that GSK3, which often promotes apoptosis, is activated during apoptosis of neural precursor cells and that inhibition of GSK3 promotes survival.
This aim will also test if inhibition of GSK3 promotes precursor cell differentiation or survival of differentiated cells. Overall, this project will continue to provide leading-edge insight into mechanisms that may underlie the pathology of mood disorders and the actions of mood stabilizers. ? ? ?
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