PMID- 23525449
OWN - NLM
STAT- MEDLINE
DCOM- 20130913
LR  - 20211021
IS  - 2047-9980 (Electronic)
IS  - 2047-9980 (Linking)
VI  - 2
IP  - 1
DP  - 2013 Feb 22
TI  - Genetic deletion of NP1 prevents hypoxic-ischemic neuronal death via reducing 
      AMPA receptor synaptic localization in hippocampal neurons.
PG  - e006098
LID - 10.1161/JAHA.112.006098 [doi]
LID - e006098
AB  - BACKGROUND: Trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid 
      receptors (AMPARs) to excitatory synapses is critical to their synaptic 
      functions. Previously, we have shown induction of neuronal pentraxin 1 (NP1) and 
      its colocalization with AMPAR subunit GluR1 in hypoxic-ischemic (HI) brain 
      injury. However, the role of NP1 in mediating GluR1 surface expression, 
      trafficking, and clustering at synapses in HI neuronal death is unclear. METHODS 
      AND RESULTS: Primary hippocampal neurons, isolated from wild-type (WT) and 
      NP1-knockout (C57BL/6 background) mice at DIV 12 to 14 were exposed to 2 to 8 
      hours of oxygen glucose deprivation (OGD)-in vitro conditions that mimic human 
      stroke. OGD exposure resulted in time-dependent induction of NP1 ( approximately 4-fold), 
      enhanced redistribution of AMAP GluR1 receptors at excitatory synapses, and 
      increased neuronal death. We observed a significant increase in surface and 
      synaptic GluR1 clusters that colocalized with PSD-95 on dendrites with a 
      simultaneous decrease in internalized GluR1. Surface cross-linking with BS(3) 
      showed enhanced membrane insertions of GluR1, and increased phosphorylation at 
      Ser-845 further supported enhanced surface availability of GluR1 after OGD. NP1 
      protein colocalized with GluR1 and PSD-95, and OGD significantly increased their 
      synaptic coclustering. Most strikingly, the genetic deletion of NP1 resulted in 
      decreases in surface GluR1 cluster density, synaptic localization, phospho-GluR1 
      (Ser-845) levels, and neuronal death after OGD compared with WT neurons. AMPA (50 
      mumol/L) induced NP1 and significant cell death in WT but not in NP1-/- neurons. 
      CONCLUSIONS: Our results indicate that NP1 plays a key role in synaptic 
      clustering of GluR1, suggesting that targeting NP1 might be a practical approach 
      to preventing ischemic brain damage.
FAU - Al Rahim, Md
AU  - Al Rahim M
AD  - Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA.
FAU - Hossain, Mir Ahamed
AU  - Hossain MA
LA  - eng
GR  - R01 NS046030/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130222
PL  - England
TA  - J Am Heart Assoc
JT  - Journal of the American Heart Association
JID - 101580524
RN  - 0 (Disks Large Homolog 4 Protein)
RN  - 0 (Dlg4 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Receptors, AMPA)
RN  - 0 (neuronal pentraxin)
RN  - 9007-41-4 (C-Reactive Protein)
RN  - EC 2.7.4.8 (Guanylate Kinases)
RN  - TFZ3H25BS1 (glutamate receptor ionotropic, AMPA 1)
SB  - IM
MH  - Animals
MH  - C-Reactive Protein/*deficiency/genetics
MH  - Cell Death
MH  - Cells, Cultured
MH  - Disks Large Homolog 4 Protein
MH  - Guanylate Kinases/metabolism
MH  - Hippocampus/*metabolism/pathology
MH  - Hypoxia-Ischemia, Brain/genetics/metabolism/pathology/*prevention & control
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Nerve Tissue Proteins/*deficiency/genetics
MH  - Phosphorylation
MH  - Protein Transport
MH  - Receptors, AMPA/*metabolism
MH  - Synapses/*metabolism/pathology
MH  - Time Factors
PMC - PMC3603251
EDAT- 2013/03/26 06:00
MHDA- 2013/09/14 06:00
PMCR- 2013/02/01
CRDT- 2013/03/26 06:00
PHST- 2013/03/26 06:00 [entrez]
PHST- 2013/03/26 06:00 [pubmed]
PHST- 2013/09/14 06:00 [medline]
PHST- 2013/02/01 00:00 [pmc-release]
AID - 2/1/e006098 [pii]
AID - jah3153 [pii]
AID - 10.1161/JAHA.112.006098 [doi]
PST - epublish
SO  - J Am Heart Assoc. 2013 Feb 22;2(1):e006098. doi: 10.1161/JAHA.112.006098.