期刊
MOLECULAR NEUROBIOLOGY
卷 49, 期 1, 页码 424-439出版社
SPRINGER
DOI: 10.1007/s12035-013-8530-7
关键词
Astrocytes; Cerebellar slice culture; Microglia; Myelination; Oligodendrocytes; Unconjugated bilirubin
资金
- FEDER
- Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/SAU-NEU/64385/2006, PEst-OE/SAU/UI4013/2011, PEst-OE/SAU/UI4013/2012]
- FCT [SFRH/BD/43885/2008, PTDC/BIA-BCM/112730/2009]
- Marie Curie Intra European Fellowship within the 7th European Community Framework Programme
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-BCM/112730/2009, SFRH/BD/43885/2008] Funding Source: FCT
The cerebellum is one of the most affected brain regions in the course of bilirubin-induced neurological dysfunction. We recently demonstrated that unconjugated bilirubin (UCB) reduces oligodendrocyte progenitor cell (OPC) survival and impairs oligodendrocyte (OL) differentiation and myelination in co-cultures of dorsal root ganglia neurons and OL. Here, we used organotypic cerebellar slice cultures, which replicate many aspects of the in vivo system, to dissect myelination defects by UCB in the presence of neuroimmune-related glial cells. Our results demonstrate that treatment of cerebellar slices with UCB reduces the number of myelinated fibres and myelin basic protein mRNA expression. Interestingly, UCB addition to slices increased the percentage of OPC and decreased mature OL content, whereas it decreased Olig1 and increased Olig2 mRNA expression. These UCB effects were associated with enhanced gliosis, revealed by an increased burden of both microglia and astrocytes. Additionally, UCB treatment led to a marked increase of tumor necrosis factor (TNF)-alpha and glutamate release, in parallel with a decrease of interleukin (IL)-6. No changes were observed relatively to IL-1 beta and S100B secretion. Curiously, both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist and TNF-alpha antibody partially prevented the myelination defects that followed UCB exposure. These data point to a detrimental role of UCB in OL maturation and myelination together with astrocytosis, microgliosis, and both inflammatory and excitotoxic responses, which collectively may account for myelin deficits following moderate to severe neonatal jaundice.
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