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Glutamate transporter EAAT2 expression is up-regulated in reactive astrocytes in human periventricular leukomalacia
Tara M Desilva1, Saraid S Billiards, Natalia S Borenstein
1Department of Neurology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Insights
In premature infants with periventricular leukomalacia (PVL), a brain disorder, glutamate transporter EAAT2 (excitatory amino acid transporter 2) is unexpectedly increased in astrocytes and macrophages. This finding may indicate a response to injury or inflammation in the developing brain.
Area of Science:
- Neuroscience
- Developmental Biology
- Neuropathology
Background:
- Periventricular leukomalacia (PVL) is a key neuropathology in premature infants, linked to cerebral palsy.
- Glutamate excitotoxicity is implicated in PVL pathogenesis, highlighting the role of glutamate transporters.
- EAAT2 (excitatory amino acid transporter 2) is crucial for regulating extracellular glutamate levels.
Purpose of the Study:
- To investigate the expression of EAAT2 in the cerebral white matter of infants with PVL compared to controls.
- To determine the cellular localization of EAAT2 in affected brain tissue.
Main Methods:
- Western blot analysis was used to quantify EAAT2 levels.
- Single- and double-label immunocytochemistry identified EAAT2-expressing cells.
- Analysis included cerebral white matter from PVL and control cases.
Main Results:
- EAAT2 expression was upregulated in PVL cases compared to controls.
- A significantly higher percentage of astrocytes expressed EAAT2 in PVL white matter (51.8%) versus controls (21.4%).
- EAAT2 was also detected in macrophages within necrotic foci in PVL cases.
Conclusions:
- EAAT2 is upregulated in reactive astrocytes and present in macrophages in PVL, which is previously unrecognized.
- This altered EAAT2 expression may represent a response to hypoxic-ischemic injury or inflammation in the immature brain.
- Findings suggest a complex role for glutamate transport in the neuropathology of PVL.
Abstract:
The major neuropathological correlate of cerebral palsy in premature infants is periventricular leukomalacia (PVL), a disorder of the immature cerebral white matter. Cerebral ischemia leading to excitotoxicity is thought to be important in the pathogenesis of this disorder, implying a critical role for glutamate transporters, the major determinants of extracellular glutamate concentration. Previously, we found that EAAT2 expression is limited primarily to premyelinating oligodendrocytes early in development and is rarely observed in astrocytes until >40 weeks. In this study, we analyzed the expression of EAAT2 in cerebral white matter from PVL and control cases. Western blot analysis suggested an up-regulation of EAAT2 in PVL compared with control cases. Single- and double-label immunocytochemistry showed a significantly higher percentage of EAAT2-immunopositive astrocytes in PVL (51.8% +/- 5.6%) compared with control white matter (21.4% +/- 5.6%; P = 0.004). Macrophages in the necrotic foci in PVL also expressed EAAT2. Premyelinating oligodendrocytes in both PVL and control cases expressed EAAT2, without qualitative difference in expression. The previously unrecognized up-regulation of EAAT2 in reactive astrocytes and its presence in macrophages in PVL reported here may reflect a response to either hypoxic-ischemic injury or inflammation.
