PMID- 16499752
OWN - NLM
STAT- MEDLINE
DCOM- 20060502
LR  - 20171116
IS  - 0013-9580 (Print)
IS  - 0013-9580 (Linking)
VI  - 47
IP  - 2
DP  - 2006 Feb
TI  - Alterations in long-term seizure susceptibility and the complex of PSD-95 with 
      NMDA receptor from animals previously exposed to perinatal hypoxia.
PG  - 288-96
AB  - PURPOSE: Perinatal hypoxia is an important cause of brain injury in the newborn 
      and has consequences that are potentially devastating and life-long, such as an 
      increased risk of epilepsy in later life. The postsynaptic density (PSD) is a 
      cytoskeletal specialization involved in the anchoring of neurotransmitter 
      receptors and in regulating the response of postsynaptic neurons to synaptic 
      stimulation. The postsynaptic protein PSD-95 binds to the N-methyl-D-aspartate 
      receptor (NMDAR) subunit, and hence activates cascades of NMDAR-mediated events, 
      such as cyclic adenosine monophosphate (cAMP)-responsive element binding protein 
      phosphorylation at serine-133 (pCREB(Serine-133)). Here we studied the effect of 
      perinatal hypoxia on protein interactions involving PSD-95 and the NMDAR, as well 
      as pCREB(Ser-133) expression at an age when the animals show increased seizure 
      susceptibility. METHODS: Rats were assigned randomly to the control rats or the 
      rats exposed to transient global hypoxia at postnatal day 10 (P10). At P45, some 
      rats from both groups were treated with pentylenetetrazol (PTZ) intraperitoneally 
      to test the seizure threshold, and others were studied for neuronal loss, 
      pCREB(Serine-133), PSD-95, and NMDAR expressions in the midbrain, temporal 
      cortex, and hippocampal CA1 subfield by using immunohistochemistry, 
      co-immunoprecipitation, and immunoblotting techniques, respectively. RESULTS: The 
      rats with prior exposure to perinatal hypoxia exhibited increased seizure 
      susceptibility to PTZ, compared with the control rats. Associated with this 
      long-term change in seizure susceptibility, selective neuronal loss was observed 
      in the midbrain region while pCREB(Ser-133) expression was reduced in the 
      midbrain, temporal cortex, and hippocampal CA1 subfield. Perinatal hypoxia led to 
      a decrease in PSD-95 expression in the both midbrain and hippocampal CA1 
      subfield, with the exception of temporal cortex. Furthermore, the association 
      between PSD-95 and NMDAR subunits (NR1, NR2A, and NR2B) in the hippocampal CA1 
      was also markedly altered by perinatal hypoxia. CONCLUSIONS: This study 
      demonstrates that the decrease in several protein complexes that are essential 
      components of the postsynaptic apparatus is associated with the observed increase 
      in seizure susceptibility in adult rats with prior exposure to perinatal hypoxia. 
      The results indicate that reductions in PSD-95 expression, PSD-95 binding of 
      NMDAR subunits, and subsequent NMDAR-mediated CREB phosphorylation, particularly 
      in hippocampal CA1, are long-term consequences of perinatal hypoxia and may, at 
      least in part, contribute to perinatal hypoxia-induced reduction in seizure 
      threshold.
FAU - Chen, Wu-Fu
AU  - Chen WF
AD  - Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 
      Taiwan.
FAU - Chang, Hong
AU  - Chang H
FAU - Huang, Li-Tung
AU  - Huang LT
FAU - Lai, Ming-Chi
AU  - Lai MC
FAU - Yang, Chun-Hwa
AU  - Yang CH
FAU - Wan, Tz-Hisung
AU  - Wan TH
FAU - Yang, San-Nan
AU  - Yang SN
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Disks Large Homolog 4 Protein)
RN  - 0 (Dlg4 protein, rat)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 452VLY9402 (Serine)
RN  - E0399OZS9N (Cyclic AMP)
RN  - WM5Z385K7T (Pentylenetetrazole)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Brain/*metabolism
MH  - Cyclic AMP/metabolism
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Disease Models, Animal
MH  - Disease Susceptibility
MH  - Disks Large Homolog 4 Protein
MH  - Hippocampus/metabolism
MH  - Hypoxia, Brain/complications/*metabolism/physiopathology
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Intracellular Signaling Peptides and Proteins/*metabolism/physiology
MH  - Membrane Proteins/*metabolism/physiology
MH  - Mesencephalon/metabolism
MH  - Pentylenetetrazole
MH  - Phosphorylation
MH  - Protein Binding
MH  - Random Allocation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism/physiology
MH  - Risk Factors
MH  - Seizures/chemically induced/*etiology/*metabolism
MH  - Serine/metabolism
MH  - Temporal Lobe/metabolism
EDAT- 2006/02/28 09:00
MHDA- 2006/05/04 09:00
CRDT- 2006/02/28 09:00
PHST- 2006/02/28 09:00 [pubmed]
PHST- 2006/05/04 09:00 [medline]
PHST- 2006/02/28 09:00 [entrez]
AID - EPI420 [pii]
AID - 10.1111/j.1528-1167.2006.00420.x [doi]
PST - ppublish
SO  - Epilepsia. 2006 Feb;47(2):288-96. doi: 10.1111/j.1528-1167.2006.00420.x.