PMID- 27326668
OWN - NLM
STAT- MEDLINE
DCOM- 20180227
LR  - 20181113
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 94
DP  - 2016 Oct
TI  - Maternal inflammation leads to impaired glutamate homeostasis and up-regulation 
      of glutamate carboxypeptidase II in activated microglia in the fetal/newborn 
      rabbit brain.
PG  - 116-28
LID - S0969-9961(16)30143-7 [pii]
LID - 10.1016/j.nbd.2016.06.010 [doi]
AB  - 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-beta1 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.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Zhang, Zhi
AU  - Zhang Z
AD  - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of 
      Medicine, 1800 Orleans St, Baltimore, MD 21287, USA.
FAU - Bassam, Bassam
AU  - Bassam B
AD  - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of 
      Medicine, 1800 Orleans St, Baltimore, MD 21287, USA.
FAU - Thomas, Ajit G
AU  - Thomas AG
AD  - Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, 1800 Orleans St, 
      Baltimore, MD 21287, USA.
FAU - Williams, Monica
AU  - Williams M
AD  - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of 
      Medicine, 1800 Orleans St, Baltimore, MD 21287, USA.
FAU - Liu, Jinhuan
AU  - Liu J
AD  - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of 
      Medicine, 1800 Orleans St, Baltimore, MD 21287, USA.
FAU - Nance, Elizabeth
AU  - Nance E
AD  - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of 
      Medicine, 1800 Orleans St, Baltimore, MD 21287, USA.
FAU - Rojas, Camilo
AU  - Rojas C
AD  - Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, 1800 Orleans St, 
      Baltimore, MD 21287, USA.
FAU - Slusher, Barbara S
AU  - Slusher BS
AD  - Neurology, Johns Hopkins School of Medicine, 1800 Orleans St, Baltimore, MD 
      21287, USA; Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, 1800 
      Orleans St, Baltimore, MD 21287, USA.
FAU - Kannan, Sujatha
AU  - Kannan S
AD  - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of 
      Medicine, 1800 Orleans St, Baltimore, MD 21287, USA. Electronic address: 
      skannan3@jhmi.edu.
LA  - eng
GR  - P30 MH075673/MH/NIMH NIH HHS/United States
GR  - R01 CA161056/CA/NCI NIH HHS/United States
GR  - R01 EB018306/EB/NIBIB NIH HHS/United States
GR  - R01 HD069562/HD/NICHD NIH HHS/United States
PT  - Journal Article
DEP - 20160617
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 3.4.17.21 (Glutamate Carboxypeptidase II)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Astrocytes/metabolism
MH  - Brain/*metabolism
MH  - Cytokines/metabolism
MH  - Female
MH  - Glutamate Carboxypeptidase II/*metabolism
MH  - Homeostasis/*physiology
MH  - Inflammation/*metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Microglia/*metabolism
MH  - Pregnancy
MH  - Rabbits
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
MH  - Up-Regulation
PMC - PMC5394739
MID - NIHMS800712
OTO - NOTNLM
OT  - Astrocytes
OT  - Cerebral palsy
OT  - Glutamate
OT  - Glutamate carboxypeptidase II (GCPII)
OT  - Microglia
OT  - Periventricular leukomalacia
OT  - Rabbit
EDAT- 2016/06/22 06:00
MHDA- 2018/02/28 06:00
PMCR- 2017/10/01
CRDT- 2016/06/22 06:00
PHST- 2016/01/13 00:00 [received]
PHST- 2016/06/05 00:00 [revised]
PHST- 2016/06/16 00:00 [accepted]
PHST- 2016/06/22 06:00 [entrez]
PHST- 2016/06/22 06:00 [pubmed]
PHST- 2018/02/28 06:00 [medline]
PHST- 2017/10/01 00:00 [pmc-release]
AID - S0969-9961(16)30143-7 [pii]
AID - 10.1016/j.nbd.2016.06.010 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2016 Oct;94:116-28. doi: 10.1016/j.nbd.2016.06.010. Epub 2016 Jun 
      17.