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

Chiye Aoki, Joyce Lee, Hermina Nedelescu, Tunazzina Ahmed, Angela Ho, Jie Shen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)512-523
Number of pages12
JournalJournal of Comparative Neurology
Volume517
Issue number4
DOIs
StatePublished - Dec 1 2009

Fingerprint

Presenilin-2
Presenilins
Presenilin-1
Synapses
Alzheimer Disease
Spine
Neuronal Plasticity
Post-Synaptic Density
Pyramidal Cells
Brain
Dendrites
N-Methyl-D-Aspartate Receptors
Microscopy
Hippocampus
Immunohistochemistry
NR2A NMDA receptor
Electrons
Depression
Phenotype
Light

Keywords

  • Alzheimer's disease
  • Animal model
  • CA1
  • Electron microscopy
  • Hippocampus
  • Immunocytochemistry
  • Mouse
  • Neurodegeneration
  • NR2B
  • Synapse density
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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. / Aoki, Chiye; Lee, Joyce; Nedelescu, Hermina; Ahmed, Tunazzina; Ho, Angela; Shen, Jie.

In: Journal of Comparative Neurology, Vol. 517, No. 4, 01.12.2009, p. 512-523.

Research output: Contribution to journalArticle

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abstract = "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.",
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