PMID- 19795494
OWN - NLM
STAT- MEDLINE
DCOM- 20091215
LR  - 20230520
IS  - 1096-9861 (Electronic)
IS  - 0021-9967 (Print)
IS  - 0021-9967 (Linking)
VI  - 517
IP  - 4
DP  - 2009 Dec 1
TI  - Increased levels of NMDA receptor NR2A subunits at pre- and postsynaptic sites of 
      the hippocampal CA1: an early response to conditional double knockout of 
      presenilin 1 and 2.
PG  - 512-23
LID - 10.1002/cne.22151 [doi]
AB  - Greater than 90% of familial Alzheimer's disease (AD) is linked to mutations of 
      presenilin (PS), and the loss of PS function altogether within mouse brains by 
      conditional double knockout of the PS 1 and 2 genes (PS-cDKO) leads to 
      age-dependent emergence of AD phenotypes, including neurodegeneration and reduced 
      synaptic plasticity in the hippocampal CA1. The goal of our study was to identify 
      the ultrastructural and molecular changes at synapses in the hippocampal CA1 of 
      this PS-cDKO mouse model of AD. We examined the asymmetric (excitatory) synapses 
      formed on apical dendrites of CA1 pyramidal neurons at 2 months postnatal, an age 
      when AD-like symptoms emerge but brain morphology, as assessed by light 
      microscopy, is still normal. Our quantitative electron microscopic analyses 
      confirm that PS-cDKO hippocampi at 2 months postnatal do not yet exhibit synapse 
      losses or spine size alterations. However, immunocytochemistry reveals that the 
      same region exhibits a 28% increase in the proportion of spines labeled for the 
      NR2A subunits of NMDA receptors (NMDAR), with a 31% increase specifically at 
      postsynaptic densities and a concomitant reduction of these subunits at 
      nonsynaptic sites within spine heads. In contrast, no change in levels or the 
      distribution pattern of NR2B subunit levels were detected within spine heads. 
      Presynaptically, NR2A levels are elevated at axo-spinous junctions and these may 
      contribute to the timing-dependent, long-term depression. These observations 
      point to an early-onset trapping of NMDAR at synapses that are subtle but may 
      underlie the reduced synaptic plasticity at 2 months of age and excitotoxicity at 
      later stages.
FAU - Aoki, Chiye
AU  - Aoki C
AD  - Center for Neural Science, New York University, New York, NY 10003, USA. 
      ca3@nyu.edu
FAU - Lee, Joyce
AU  - Lee J
FAU - Nedelescu, Hermina
AU  - Nedelescu H
FAU - Ahmed, Tunazzina
AU  - Ahmed T
FAU - Ho, Angela
AU  - Ho A
FAU - Shen, Jie
AU  - Shen J
LA  - eng
GR  - R01 DA009618/DA/NIDA NIH HHS/United States
GR  - NS41783/NS/NINDS NIH HHS/United States
GR  - R01 NS041091/NS/NINDS NIH HHS/United States
GR  - P30 EY013079/EY/NEI NIH HHS/United States
GR  - RF1 NS041783/NS/NINDS NIH HHS/United States
GR  - R25 NS080686/NS/NINDS NIH HHS/United States
GR  - R01 EY013145-04/EY/NEI NIH HHS/United States
GR  - R01 NS041783-08/NS/NINDS NIH HHS/United States
GR  - 2R01DA009618-01A1/DA/NIDA NIH HHS/United States
GR  - R01 NS041783/NS/NINDS NIH HHS/United States
GR  - R01 EY013145/EY/NEI NIH HHS/United States
GR  - P30 EY013079-109003/EY/NEI NIH HHS/United States
GR  - R01 NS041091-04/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Comp Neurol
JT  - The Journal of comparative neurology
JID - 0406041
RN  - 0 (NR2A NMDA receptor)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (Presenilin-1)
RN  - 0 (Presenilin-2)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 2.7.11.17 (Camk2a protein, mouse)
SB  - IM
MH  - Animals
MH  - CA1 Region, Hippocampal/*cytology
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics
MH  - Dendrites/metabolism
MH  - Gene Expression Regulation/*genetics
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Immunoelectron/methods
MH  - Models, Biological
MH  - Presenilin-1/*deficiency
MH  - Presenilin-2/*deficiency
MH  - Presynaptic Terminals/metabolism/ultrastructure
MH  - Receptors, N-Methyl-D-Aspartate/genetics/*metabolism
MH  - Synapses/*metabolism/ultrastructure
PMC - PMC2796344
MID - NIHMS160474
EDAT- 2009/10/02 06:00
MHDA- 2009/12/16 06:00
PMCR- 2009/12/21
CRDT- 2009/10/02 06:00
PHST- 2009/10/02 06:00 [entrez]
PHST- 2009/10/02 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2009/12/21 00:00 [pmc-release]
AID - 10.1002/cne.22151 [doi]
PST - ppublish
SO  - J Comp Neurol. 2009 Dec 1;517(4):512-23. doi: 10.1002/cne.22151.