Astrocyte dysfunction and excessive activation of glutamatergic systems have been implicated in a number of
neurologic disorders, including
periventricular leukomalacia (PVL) and
cerebral palsy (CP). However, the role of
chorioamnionitis on
glutamate homeostasis in the fetal and neonatal brains is not clearly understood. We have previously shown that intrauterine
endotoxin administration results in intense microglial 'activation' and increased pro-inflammatory
cytokines in the periventricular region (PVR) of the neonatal rabbit brain. In this study, we assessed the effect of maternal
inflammation on key components of the
glutamate pathway and its relationship to astrocyte and microglial activation in the fetal and neonatal New Zealand white rabbit brain. We found that intrauterine
endotoxin exposure at gestational day 28 (G28) induced acute and prolonged
glutamate elevation in the PVR of fetal (G29, 1day post-injury) and postnatal day 1 (PND1, 3days post-injury) brains along with prominent morphological changes in the astrocytes (
soma hypertrophy and retracted processes) in the white matter tracts. There was a significant increase in
glutaminase and
N-Methyl-d-Aspartate receptor (NMDAR) NR2 subunit expression along with decreased glial
L-glutamate transporter 1 (GLT-1) in the PVR at G29, that would promote acute dysregulation of
glutamate homeostasis. This was accompanied with significantly decreased TGF-β1 at PND1 in CP kits indicating ongoing
neuroinflammation. We also show for the first time that
glutamate carboxypeptidase II (GCPII) was significantly increased in the activated microglia at the periventricular white matter area in both G29 and PND1 CP kits. This was confirmed by in vitro studies demonstrating that LPS activated primary microglia markedly upregulate GCPII enzymatic activity. These results suggest that maternal intrauterine
endotoxin exposure results in early onset and long-lasting dysregulation of
glutamate homeostasis, which may be mediated by impaired astrocyte function and GCPII upregulation in activated microglia.