Limits...
NMDA-receptor activation but not ion flux is required for amyloid-beta induced synaptic depression.

Tamburri A, Dudilot A, Licea S, Bourgeois C, Boehm J - PLoS ONE (2013)

Bottom Line: Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects.This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux.It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

View Article: PubMed Central - PubMed

Affiliation: Département de Physiologie, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada.

ABSTRACT
Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

Show MeSH

Related in: MedlinePlus

Aβ depresses synaptic transmission.(A) Changes in normalized EPSC amplitudes plotted against time in presence of Aβ oligomers, vehicle, scrambled and monomeric Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the experiment. After baseline recording, Aβ (red trace), vehicle (blue trace), scrambled Aβ (sAβ, green trace) or monomeric Aβ (mAβ, yellow trace) were applied to the bath solution. The arrow indicates when either the peptides or the vehicle solution was bath applied. Averaged traces taken during baseline recording and 15 min after peptide or vehicle application (horizontal black bars in the scatter blot) are shown above the graph. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Quantification of the experiment shown in A. Acute Aβ perfusion leads to a fast induction of synaptic depression. (*p<0.01, n = 6).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3672194&req=5

pone-0065350-g002: Aβ depresses synaptic transmission.(A) Changes in normalized EPSC amplitudes plotted against time in presence of Aβ oligomers, vehicle, scrambled and monomeric Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the experiment. After baseline recording, Aβ (red trace), vehicle (blue trace), scrambled Aβ (sAβ, green trace) or monomeric Aβ (mAβ, yellow trace) were applied to the bath solution. The arrow indicates when either the peptides or the vehicle solution was bath applied. Averaged traces taken during baseline recording and 15 min after peptide or vehicle application (horizontal black bars in the scatter blot) are shown above the graph. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Quantification of the experiment shown in A. Acute Aβ perfusion leads to a fast induction of synaptic depression. (*p<0.01, n = 6).

Mentions: We therefore acutely perfused oligomeric Aβ (0.1 µM, Fig. 1a) and analyzed its effects on evoked field potentials. After having established a stable baseline recording for 20 min, we perfused the slice cultures with oligomeric Aβ for 20 min. As seen in Figure 1 b and c, Aβ oligomers induced a significant synaptic depression within 10 min of exposure. We did not observe a difference in the fiber volley amplitude upon Aβ perfusion (Fig. 1 b and c), indicating that the acute Aβ-dependent synaptic depression does not act presynaptically. To further analyze the synaptic mechanisms of acute Aβ induced synaptic depression, we recorded evoked basal synaptic transmission in CA1 neurons in whole-cell patch clamp configuration (−60 mV holding potential) by stimulating the Schaffer collaterals. After 3 min of baseline recording, we perfused slices with oligomeric Aβ. As seen in Figure j, we observed a statistically significant synaptic depression within 10–15 minutes after Aβ application. This depression was specific for Aβ oligomers, since the scrambled form of Aβ (randomized Aβ amino acid sequence peptide), the monomeric Aβ as well as vehicle alone had no effect on basal synaptic transmission (Fig. 2a and 2b).


NMDA-receptor activation but not ion flux is required for amyloid-beta induced synaptic depression.

Tamburri A, Dudilot A, Licea S, Bourgeois C, Boehm J - PLoS ONE (2013)

Aβ depresses synaptic transmission.(A) Changes in normalized EPSC amplitudes plotted against time in presence of Aβ oligomers, vehicle, scrambled and monomeric Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the experiment. After baseline recording, Aβ (red trace), vehicle (blue trace), scrambled Aβ (sAβ, green trace) or monomeric Aβ (mAβ, yellow trace) were applied to the bath solution. The arrow indicates when either the peptides or the vehicle solution was bath applied. Averaged traces taken during baseline recording and 15 min after peptide or vehicle application (horizontal black bars in the scatter blot) are shown above the graph. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Quantification of the experiment shown in A. Acute Aβ perfusion leads to a fast induction of synaptic depression. (*p<0.01, n = 6).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672194&req=5

pone-0065350-g002: Aβ depresses synaptic transmission.(A) Changes in normalized EPSC amplitudes plotted against time in presence of Aβ oligomers, vehicle, scrambled and monomeric Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the experiment. After baseline recording, Aβ (red trace), vehicle (blue trace), scrambled Aβ (sAβ, green trace) or monomeric Aβ (mAβ, yellow trace) were applied to the bath solution. The arrow indicates when either the peptides or the vehicle solution was bath applied. Averaged traces taken during baseline recording and 15 min after peptide or vehicle application (horizontal black bars in the scatter blot) are shown above the graph. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Quantification of the experiment shown in A. Acute Aβ perfusion leads to a fast induction of synaptic depression. (*p<0.01, n = 6).
Mentions: We therefore acutely perfused oligomeric Aβ (0.1 µM, Fig. 1a) and analyzed its effects on evoked field potentials. After having established a stable baseline recording for 20 min, we perfused the slice cultures with oligomeric Aβ for 20 min. As seen in Figure 1 b and c, Aβ oligomers induced a significant synaptic depression within 10 min of exposure. We did not observe a difference in the fiber volley amplitude upon Aβ perfusion (Fig. 1 b and c), indicating that the acute Aβ-dependent synaptic depression does not act presynaptically. To further analyze the synaptic mechanisms of acute Aβ induced synaptic depression, we recorded evoked basal synaptic transmission in CA1 neurons in whole-cell patch clamp configuration (−60 mV holding potential) by stimulating the Schaffer collaterals. After 3 min of baseline recording, we perfused slices with oligomeric Aβ. As seen in Figure j, we observed a statistically significant synaptic depression within 10–15 minutes after Aβ application. This depression was specific for Aβ oligomers, since the scrambled form of Aβ (randomized Aβ amino acid sequence peptide), the monomeric Aβ as well as vehicle alone had no effect on basal synaptic transmission (Fig. 2a and 2b).

Bottom Line: Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects.This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux.It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

View Article: PubMed Central - PubMed

Affiliation: Département de Physiologie, Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec, Canada.

ABSTRACT
Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

Show MeSH
Related in: MedlinePlus