The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter.
The major brain abnormality underlying cerebral palsy in premature infants is periventricular leukomalacia (PVL), a lesion of the immature cerebral white matter. Oligodendrocyte precursors (pre-OLs; O4(+)O1(-)) predominate in human cerebral white matter during the peak time frame for PVL (24-32 gestational weeks) and are vulnerable to excitotoxicity. We hypothesize that PVL reflects, in part, excitotoxicity to pre-OLs resulting from cerebral ischemia/reperfusion. Reversal of glutamate transport in the setting of energy failure is a major source of pathologic accumulation of extracellular glutamate. Here, we identify and localize the glutamate transporters in human cerebral white matter during the age range of PVL. In situ hybridization was performed with digoxigenin-labeled probes directed against the full-length coding regions of EAAT1, EAAT2, and EAAT3. EAAT2 mRNA was abundant in human fetal white matter during the period of peak incidence of PVL and virtually disappeared by 2 postnatal months. Its developmental profile differed significantly from that of both EAAT1 and EAAT3 mRNA. Immunoblotting demonstrated that EAAT2 protein was highly expressed in early development relative to adult values. Double-label immunocytochemistry detected EAAT2 in OLs but not astrocytes or axons in the human fetal white matter. We conclude that transient expression of EAAT2 occurs during the window of peak vulnerability for PVL, suggesting that this developmentally up-regulated transporter may be a major source of extracellular glutamate in ischemic injury to the cerebral white matter of the preterm infant.
Desilva
Tara M
TM
Neurobiology Program, Children's Hospital Boston, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kinney
Hannah C
HC
Borenstein
Natalia S
NS
Trachtenberg
Felicia L
FL
Irwin
Nina
N
Volpe
Joseph J
JJ
Rosenberg
Paul A
PA
D000328:Adult; D000368:Aged; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D003423:Critical Period, Psychological; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008875:Middle Aged; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D014018:Tissue Distribution
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D012333:RNA, Messenger