Activation of glycogen synthase kinase 3 beta (GSK-3 beta) by platelet activating factor mediates migration and cell death in cerebellar granule neurons

Children with vertically acquired HIV-1 can present with a rapidly progress ive encephalopathy and neuronal apoptosis in the first 12-18 months of life . Furthermore, abnormal prenatal platelet activating factor (PAF) signallin g may result in lissencephaly, a disorder of neuronal migration. PAF, produ ced from human immunodeficiency virus type 1 (HIV-1) -infected brain-reside nt macrophages, induces neuronal apoptosis in cultured cerebellar granule n eurons (CGNs) in part by activating glycogen synthase kinase 3 beta (GSK-3 beta). However, PAF can also inhibit migration of CGNs that are dispersed a nd allowed to reaggregate. Therefore, we investigated the biological effect s following activation of GSK-3 beta by PAF, and whether these effects were dependent on the culture conditions of the CGNs. We show here that activat ion of neuronal GSK-3 beta by PAF is receptor-specific, with similar kineti cs of activation in both monolayer cultures of CGNs that have ceased to mig rate and reaggregate cultures of CGNs that are actively migrating. However, PAF receptor activation in reaggregated CGNs inhibits neuronal migration a nd induces approximately half the level of neuronal apoptosis compared with PAF-treated CGN cultures that have ceased to migrate. PAF-mediated inhibit ion of neuronal migration in reaggregated CGNs or induction of apoptosis in CGNs that have ceased to migrate can be reversed by either PAF receptor an tagonists, or the GSK-3 beta inhibitors lithium or valproic acid, in a dose -dependent manner. Abnormal PAF signalling that results in GSK-3 beta overa ctivation may represent a common mechanism for pathological defects in neur onal migration in the prenatal period and neuronal apoptosis in the postnat al period.