Abstract
Neuron-specific enolase (NSE) is a glycolytic isoenzyme found in mature neurons and cells of neuronal origin. Injecting adeno-associated virus serotype 9 (AAV9) vectors carrying the NSE promoter into the cerebellar cortex is likely to cause the specific transduction of neuronal cells, such as Purkinje cells (PCs) and interneurons, but not Bergmann glia (BG). However, we found BG-predominant transduction without PC transduction along a traumatic needle tract for viral injection. The enhancement of neuroinflammation by the co-application of lipopolysaccharide (LPS) with AAV9 significantly expanded the BG-predominant area concurrently with the potentiated microglial activation. The BG-predominant transduction was gradually replaced by the PC-predominant transduction as the neuroinflammation dissipated. Experiments using glioma cell cultures revealed significant activation of the NSE promoter due to glucose deprivation, suggesting that intracellularly stored glycogen is metabolized through the glycolytic pathway for energy. Activation of the glycolytic enzyme promoter in BG concurrently with inactivation in PC may have pathophysiological significance for the production of lactate in activated BG and the utilization of lactate, which is provided by the BG-PC lactate shuttle, as a primary energy resource in injured PCs.
Highlights
As expected in the neuron-specific Neuron-specific enolase (NSE) promoter, fluorescent microscopy of region 1 in the lobule 9 (Fig. 1A–C) revealed efficient and strong GFP expression predominantly in the PCs, which were immunolabelled for parvalbumin
Given that the alteration in the cell-type specificity of the NSE promoter property is caused by mechanical damage and subsequent local inflammation, numerous activated microglia should be observed around BG-dominant transduction areas
These results suggest that local neuroinflammation and subsequent microglial invasion play key roles in switching the cell type in which the NSE promoter functions from PC to BG
Summary
As expected in the neuron-specific NSE promoter, fluorescent microscopy of region 1 in the lobule 9 (Fig. 1A–C) revealed efficient and strong GFP expression predominantly in the PCs (arrows, Fig. 1B,H), which were immunolabelled for parvalbumin (data not shown). Almost no S100-positive astrocytes in the granule cell layer expressed GFP in region 1 (PC-predominant transduction area), whereas numerous GFP-expressing S100-positive astrocytes were observed in region 2 (BG-predominant transduction area) (Supplementary Figure 1), suggesting that the NSE promoter is activated in BGs but in astrocytes in general.
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