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 has no effect on NMDA-receptor mediated ion conductance.(A) Normalized EPSC amplitudes plotted against time in presence of CNQX and Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the duration of the experiments. Following baseline recording, CNQX was applied to the bath to block AMPA-receptor dependent currents (arrow on the left). Following the sharp decrease in the EPSC amplitude, Aβ oligomers were applied (arrow on the right). Averaged traces taken during baseline recording (min 2), after CNQX application (min 12) and after Aβ application (min 25) are shown above the graph. There is no evident difference between currents recorded immediately before Aβ application and currents recorded 10 minutes following Aβ application (n = 6). Color legend: black: currents recorded before CNQX application; red: currents recorded before Aβ application; blue: currents recorded after Aβ application. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Normalized NMDA-receptor I/V curve recorded in presence or absence of Aβ oligomers. Evoked synaptic responses of CA1 pyramidal neurons were recorded at −60 mV. Next, CNQX was bath applied to block AMPA-receptor currents. Following AMPA-receptor blockade, either vehicle or Aβ was bath applied. 15 min after Aβ application, evoked EPSCs (now dependent on NMDA-receptor responses) were recorded at different holding potentials (steps of 10 mV increments from −60 to +20 mV holding potential). Calculating the ratio of NMDA-receptor responses vs. the initial AMPA-receptor response was used to normalize the NMDA-receptor currents from different experiments. No noticeable difference in NMDA-receptor responses was found between neurons treated with vehicle vs. Aβ oligomers (n = 5 per group).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3672194&req=5

pone-0065350-g005: Aβ has no effect on NMDA-receptor mediated ion conductance.(A) Normalized EPSC amplitudes plotted against time in presence of CNQX and Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the duration of the experiments. Following baseline recording, CNQX was applied to the bath to block AMPA-receptor dependent currents (arrow on the left). Following the sharp decrease in the EPSC amplitude, Aβ oligomers were applied (arrow on the right). Averaged traces taken during baseline recording (min 2), after CNQX application (min 12) and after Aβ application (min 25) are shown above the graph. There is no evident difference between currents recorded immediately before Aβ application and currents recorded 10 minutes following Aβ application (n = 6). Color legend: black: currents recorded before CNQX application; red: currents recorded before Aβ application; blue: currents recorded after Aβ application. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Normalized NMDA-receptor I/V curve recorded in presence or absence of Aβ oligomers. Evoked synaptic responses of CA1 pyramidal neurons were recorded at −60 mV. Next, CNQX was bath applied to block AMPA-receptor currents. Following AMPA-receptor blockade, either vehicle or Aβ was bath applied. 15 min after Aβ application, evoked EPSCs (now dependent on NMDA-receptor responses) were recorded at different holding potentials (steps of 10 mV increments from −60 to +20 mV holding potential). Calculating the ratio of NMDA-receptor responses vs. the initial AMPA-receptor response was used to normalize the NMDA-receptor currents from different experiments. No noticeable difference in NMDA-receptor responses was found between neurons treated with vehicle vs. Aβ oligomers (n = 5 per group).

Mentions: To analyze changes in NMDA-R dependent synaptic transmission, we recorded isolated NMDA-R responses by employing the AMPA/Kainate-receptor inhibitor CNQX. As seen in Figure 5a, CNQX completely blocks AMPA-receptor dependent transmission. After AMPA-receptor dependent transmission was blocked, we perfused oligomeric Aβ for 15 min and recorded evoked synaptic responses. However, we did not observe any increase in NMDA-R mediated synaptic transmission, as we would have expected if Aβ could increase ion leakage through the NMDA-receptor.


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 has no effect on NMDA-receptor mediated ion conductance.(A) Normalized EPSC amplitudes plotted against time in presence of CNQX and Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the duration of the experiments. Following baseline recording, CNQX was applied to the bath to block AMPA-receptor dependent currents (arrow on the left). Following the sharp decrease in the EPSC amplitude, Aβ oligomers were applied (arrow on the right). Averaged traces taken during baseline recording (min 2), after CNQX application (min 12) and after Aβ application (min 25) are shown above the graph. There is no evident difference between currents recorded immediately before Aβ application and currents recorded 10 minutes following Aβ application (n = 6). Color legend: black: currents recorded before CNQX application; red: currents recorded before Aβ application; blue: currents recorded after Aβ application. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Normalized NMDA-receptor I/V curve recorded in presence or absence of Aβ oligomers. Evoked synaptic responses of CA1 pyramidal neurons were recorded at −60 mV. Next, CNQX was bath applied to block AMPA-receptor currents. Following AMPA-receptor blockade, either vehicle or Aβ was bath applied. 15 min after Aβ application, evoked EPSCs (now dependent on NMDA-receptor responses) were recorded at different holding potentials (steps of 10 mV increments from −60 to +20 mV holding potential). Calculating the ratio of NMDA-receptor responses vs. the initial AMPA-receptor response was used to normalize the NMDA-receptor currents from different experiments. No noticeable difference in NMDA-receptor responses was found between neurons treated with vehicle vs. Aβ oligomers (n = 5 per group).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0065350-g005: Aβ has no effect on NMDA-receptor mediated ion conductance.(A) Normalized EPSC amplitudes plotted against time in presence of CNQX and Aβ. Neurons were patched and held at −60 mV and responses were evoked throughout the duration of the experiments. Following baseline recording, CNQX was applied to the bath to block AMPA-receptor dependent currents (arrow on the left). Following the sharp decrease in the EPSC amplitude, Aβ oligomers were applied (arrow on the right). Averaged traces taken during baseline recording (min 2), after CNQX application (min 12) and after Aβ application (min 25) are shown above the graph. There is no evident difference between currents recorded immediately before Aβ application and currents recorded 10 minutes following Aβ application (n = 6). Color legend: black: currents recorded before CNQX application; red: currents recorded before Aβ application; blue: currents recorded after Aβ application. Scale bars: horizontal 0.1 s; vertical 10 pA. (B) Normalized NMDA-receptor I/V curve recorded in presence or absence of Aβ oligomers. Evoked synaptic responses of CA1 pyramidal neurons were recorded at −60 mV. Next, CNQX was bath applied to block AMPA-receptor currents. Following AMPA-receptor blockade, either vehicle or Aβ was bath applied. 15 min after Aβ application, evoked EPSCs (now dependent on NMDA-receptor responses) were recorded at different holding potentials (steps of 10 mV increments from −60 to +20 mV holding potential). Calculating the ratio of NMDA-receptor responses vs. the initial AMPA-receptor response was used to normalize the NMDA-receptor currents from different experiments. No noticeable difference in NMDA-receptor responses was found between neurons treated with vehicle vs. Aβ oligomers (n = 5 per group).
Mentions: To analyze changes in NMDA-R dependent synaptic transmission, we recorded isolated NMDA-R responses by employing the AMPA/Kainate-receptor inhibitor CNQX. As seen in Figure 5a, CNQX completely blocks AMPA-receptor dependent transmission. After AMPA-receptor dependent transmission was blocked, we perfused oligomeric Aβ for 15 min and recorded evoked synaptic responses. However, we did not observe any increase in NMDA-R mediated synaptic transmission, as we would have expected if Aβ could increase ion leakage through the NMDA-receptor.

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