期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 13, 期 10, 页码 1913-1922出版社
BLACKWELL SCIENCE LTD
DOI: 10.1046/j.0953-816x.2001.01572.x
关键词
apoptosis; glycogen synthase kinase 3 beta (GSK-3 beta); human immunodeficiency virus type 1 (HIV-1); neuronal migration; platelet activating factor
资金
- NIMH NIH HHS [R01 MH56838, P01 MH57556] Funding Source: Medline
- NINDS NIH HHS [R01 NS40315] Funding Source: Medline
Children with vertically acquired HIV-1 can present with a rapidly progressive encephalopathy and neuronal apoptosis in the first 12-18 months of life. Furthermore, abnormal prenatal platelet activating factor (PAF) signalling may result in lissencephaly, a disorder of neuronal migration. PAF, produced from human immunodeficiency virus type 1 (HIV-1) -infected brain-resident macrophages, induces neuronal apoptosis in cultured cerebellar granule neurons (CGNs) in part by activating glycogen synthase kinase 3 beta (GSK-3 beta). However, PAF can also inhibit migration of CGNs that are dispersed and allowed to reaggregate. Therefore, we investigated the biological effects 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 activation of neuronal GSK-3 beta by PAF is receptor-specific, with similar kinetics of activation in both monolayer cultures of CGNs that have ceased to migrate and reaggregate cultures of CGNs that are actively migrating. However, PAF receptor activation in reaggregated CGNs inhibits neuronal migration and induces approximately half the level of neuronal apoptosis compared with PAF-treated CGN cultures that have ceased to migrate. PAF-mediated inhibition of neuronal migration in reaggregated CGNs or induction of apoptosis in CGNs that have ceased to migrate can be reversed by either PAF receptor antagonists, or the GSK-3 beta inhibitors lithium or valproic acid, in a dose-dependent manner. Abnormal PAF signalling that results in GSK-3 beta overactivation may represent a common mechanism for pathological defects in neuronal migration in the prenatal period and neuronal apoptosis in the postnatal period.
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