Platelet activating factor (PAF) is a bioactive phospholipid which plays a variety of roles in the central nervous system (CNS). A number of pathologic events, including seizures, ischemia and inflammatory reactions lead to the synaptic accumulation of PAF. In this setting, PAF can act as a mediator of neuronal injury. Excessive levels of PAF may also interfere with the normal development of the CNS, by inhibiting neuronal migration (for example, in the context of Miller-Dieker lissencephaly). Our preliminary studies have shown that PAF can upregulate the activity of glycogen synthase kinase 3-beta (GSK-3b) in primary neurons. This may be relevant to PAF's effects on neuronal survival and neuronal migration because GSK-3b has been implicated in axonal remodeling and in the regulation of the neuronal cytoskeleton, and also because activation (over expression) of GSK-3b has been demonstrated to lead to apoptosis of PC12 cells. We therefore hypothesize that PAF's effects on GSK-3b may contribute both to its neurotoxic activity and to its ability to disrupt neuronal migration. The studies proposed in this application are intended to experimentally test this hypothesis. First, the molecular mechanisms, which contribute to PAF-mediated activation of neuronal GSK-3b, will be delineated (Aim 1). Second, experiments will be conducted; to test the hypothesis that GSK-3b activation is required for PAF-mediated neurotoxicity (Aim 2). Finally, studies will be performed to determine whether GSK-3b activation is also required for PAF-mediated disruption of neuronal migration (Aim 3). Taken together, these experiments are expected to provide new insights into the regulation of GSK-3b activity in neurons, and into the role that GSK-3b may play in mediating PAF's effects on neuronal survival and neuronal migration.
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