Presenilin conditional double knockout mice exhibit decreases in drebrin a at hippocampal CA1 synapses

David Lee, Chiye Aoki

Research output: Contribution to journalArticle

Abstract

Presenilin conditional double knockout (PScDKO) mice have been used as animal models to study the development of Alzheimer's disease (AD) phenotypes. Studies to date indicate that these animals exhibit memory dysfunction and decreased synaptic plasticity before the onset of neurodegeneration. Therefore, the current study sought to examine how the loss of presenilin expression leads to these defects. Drebrin A, a neuron-specific actin-binding protein, has been shown to play an important role in the activity-dependent redistribution of the NMDA type of glutamate receptors at the synapse which, in turn, is a critical step for enabling synaptic plasticity. It is hypothesized that defects in the activity dependent redistribution of NMDA receptors in PScDKO mice may be due to loss of drebrin A. In this study, electron microscopic immunocytochemistry (EM-ICC) was used to quantify and locate drebrin A in the CA1 field of the hippocampus of PScDKO mice. The high resolution of EM-ICC allowed for differentiation between drebrin A at the synapse and at nonsynaptic sites, the latter of which would reflect the protein's role in regulating the reserve or degradative pool of NMDA receptors. The results here demonstrate that loss of function of presenilin in mice leads to a decrease in immunoreactivity for drebrin A at both synaptic (54% decrease, P < 0.01) and nonsynaptic areas (40% decrease, P < 0.01) and overall (44% decrease, P < 0.01). The reduction of drebrin A in both synaptic and nonsynaptic locations of the spine may implicate impairment in glutamate receptor trafficking to and from the postsynaptic plasma membrane. In addition, because of reduced drebrin A at nonsynaptic sites, the regulation of the reserve and degradative pools of glutamate receptors may also be impaired, leading to further synaptic dysfunction. Therefore, this study provides evidence to the theory that drebrin A has a causal role in compromising activity-dependent glutamate receptor trafficking in PScDKO mice. Synapse, 2012.

Original languageEnglish (US)
Pages (from-to)870-879
Number of pages10
JournalSynapse
Volume66
Issue number10
DOIs
StatePublished - Oct 2012

Fingerprint

Presenilins
Knockout Mice
Synapses
Glutamate Receptors
N-Methyl-D-Aspartate Receptors
Neuronal Plasticity
Immunohistochemistry
Electrons
Hippocampal CA1 Region
Microfilament Proteins
drebrins
Alzheimer Disease
Spine
Animal Models
Cell Membrane
Phenotype
Neurons

Keywords

  • Alzheimer's disease
  • Animal model
  • CA1
  • Drebrin A
  • Electron microscopy
  • Hippocampus
  • Immunocytochemistry
  • Mouse

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Presenilin conditional double knockout mice exhibit decreases in drebrin a at hippocampal CA1 synapses. / Lee, David; Aoki, Chiye.

In: Synapse, Vol. 66, No. 10, 10.2012, p. 870-879.

Research output: Contribution to journalArticle

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abstract = "Presenilin conditional double knockout (PScDKO) mice have been used as animal models to study the development of Alzheimer's disease (AD) phenotypes. Studies to date indicate that these animals exhibit memory dysfunction and decreased synaptic plasticity before the onset of neurodegeneration. Therefore, the current study sought to examine how the loss of presenilin expression leads to these defects. Drebrin A, a neuron-specific actin-binding protein, has been shown to play an important role in the activity-dependent redistribution of the NMDA type of glutamate receptors at the synapse which, in turn, is a critical step for enabling synaptic plasticity. It is hypothesized that defects in the activity dependent redistribution of NMDA receptors in PScDKO mice may be due to loss of drebrin A. In this study, electron microscopic immunocytochemistry (EM-ICC) was used to quantify and locate drebrin A in the CA1 field of the hippocampus of PScDKO mice. The high resolution of EM-ICC allowed for differentiation between drebrin A at the synapse and at nonsynaptic sites, the latter of which would reflect the protein's role in regulating the reserve or degradative pool of NMDA receptors. The results here demonstrate that loss of function of presenilin in mice leads to a decrease in immunoreactivity for drebrin A at both synaptic (54{\%} decrease, P < 0.01) and nonsynaptic areas (40{\%} decrease, P < 0.01) and overall (44{\%} decrease, P < 0.01). The reduction of drebrin A in both synaptic and nonsynaptic locations of the spine may implicate impairment in glutamate receptor trafficking to and from the postsynaptic plasma membrane. In addition, because of reduced drebrin A at nonsynaptic sites, the regulation of the reserve and degradative pools of glutamate receptors may also be impaired, leading to further synaptic dysfunction. Therefore, this study provides evidence to the theory that drebrin A has a causal role in compromising activity-dependent glutamate receptor trafficking in PScDKO mice. Synapse, 2012.",
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