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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.

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Related in: MedlinePlus

Aβ induced synaptic depression is dependent on synaptic stimulation.(A) Miniature EPSCs Upper traces: average of miniature events after perfusion of control (blue) or Aβ (red). Scale bars: horizontal, 5 ms; vertical 5 pA. Middle and lower traces: sample of a four seconds recording of miniature EPSC activity following perfusion of control (blue) or Aβ oligomers (red). Scale bars: horizontal 0.2 s; vertical 10 pA. (B) Perfusion of Aβ oligomers (red) does not change the amplitude (left) or the frequency (right) of recorded miniature events when compared to vehicle control (blue) (n = 20 for each condition). (C) EPSC recordings obtained by applying a paired pulse facilitation protocol under control conditions (blue trace) and after Aβ oligomers perfusion (red trace). Inter pulse interval was 30 ms. Scale bars: horizontal, 20 ms; vertical 20 pA. (D) Quantification of the experiment shown in C. Perfusion of Aβ oligomers (red) does not affect paired-pulse facilitation when compared to control (blue). The response to the second pulse was normalized by the response to the first pulse (n = 10 for each condition). (E) Aβ induced synaptic depression is dependent on synaptic stimulation. Normalized EPSCs from CA1 neurons are shown. After baseline recordings, Aβ oligomers were added to the bath solution (black arrow) and the stimulation protocol paused for 10 minutes (represented by the black bar) before being resumed for another 10 min. (F) Quantification of the experiment shown in E. Bars indicate responses recorded during baseline (blue) and in presence of Aβ (red) at different time intervals: minute 12–13 averages responses recorded immediately after stimulation was resumed; minute 22–23 averages responses 10 minutes after stimulation was resumed (i.e. 19–20 minutes after the start of Aβ perfusion) (*p<0.05, n = 8).
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pone-0065350-g003: Aβ induced synaptic depression is dependent on synaptic stimulation.(A) Miniature EPSCs Upper traces: average of miniature events after perfusion of control (blue) or Aβ (red). Scale bars: horizontal, 5 ms; vertical 5 pA. Middle and lower traces: sample of a four seconds recording of miniature EPSC activity following perfusion of control (blue) or Aβ oligomers (red). Scale bars: horizontal 0.2 s; vertical 10 pA. (B) Perfusion of Aβ oligomers (red) does not change the amplitude (left) or the frequency (right) of recorded miniature events when compared to vehicle control (blue) (n = 20 for each condition). (C) EPSC recordings obtained by applying a paired pulse facilitation protocol under control conditions (blue trace) and after Aβ oligomers perfusion (red trace). Inter pulse interval was 30 ms. Scale bars: horizontal, 20 ms; vertical 20 pA. (D) Quantification of the experiment shown in C. Perfusion of Aβ oligomers (red) does not affect paired-pulse facilitation when compared to control (blue). The response to the second pulse was normalized by the response to the first pulse (n = 10 for each condition). (E) Aβ induced synaptic depression is dependent on synaptic stimulation. Normalized EPSCs from CA1 neurons are shown. After baseline recordings, Aβ oligomers were added to the bath solution (black arrow) and the stimulation protocol paused for 10 minutes (represented by the black bar) before being resumed for another 10 min. (F) Quantification of the experiment shown in E. Bars indicate responses recorded during baseline (blue) and in presence of Aβ (red) at different time intervals: minute 12–13 averages responses recorded immediately after stimulation was resumed; minute 22–23 averages responses 10 minutes after stimulation was resumed (i.e. 19–20 minutes after the start of Aβ perfusion) (*p<0.05, n = 8).

Mentions: To further characterize the basis of Aβ induced changes in synaptic transmission, we recorded synaptic miniature events in the presence of Aβ. We perfused slice cultures for 20 min with Aβ or vehicle, added TTX for 10 min and recorded miniature events (Fig. 3a). As seen in Figure 3b, we observed no changes in miniature amplitudes or frequency in the presence of Aβ and TTX. The unchanged miniature frequency is consistent with our data showing that Aβ does not affect fiber-volley amplitudes (Fig. 1b and c) or paired-pulse facilitation (Figure 3c and d), indicating that the presynaptic site is not involved in acute Aβ dependent synaptic depression. However, the lack of change in miniature amplitudes while having previously observed synaptic depression in field recordings (Fig. 1b) as well as whole-cell patch-clamp recordings (Fig. 2a), suggested that Aβ mediated synaptic depression is dependent on synaptic stimulation. To test this hypothesis, we repeated our experiment seen in Fig. 2a, but paused external stimulation during the first 10 min of Aβ perfusion. Resuming stimulation after 10 min Aβ perfusion revealed no synaptic depression for the first minutes, indicating that Aβ induced depression is dependent on synaptic stimulation. Consequently, 5 min after resuming stimulation, synaptic transmission became significantly reduced (Figure 3e and f; the steeper induction curve of depression in comparison to Fig. 2a is most likely due to Aβ already being present at the synapse when stimulation is resumed, i.e. slices are already perfused for 10 min with Aβ). Taken together, we conclude that Aβ can rapidly induce synaptic depression, but only in the presence of sufficient synaptic activity.


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 induced synaptic depression is dependent on synaptic stimulation.(A) Miniature EPSCs Upper traces: average of miniature events after perfusion of control (blue) or Aβ (red). Scale bars: horizontal, 5 ms; vertical 5 pA. Middle and lower traces: sample of a four seconds recording of miniature EPSC activity following perfusion of control (blue) or Aβ oligomers (red). Scale bars: horizontal 0.2 s; vertical 10 pA. (B) Perfusion of Aβ oligomers (red) does not change the amplitude (left) or the frequency (right) of recorded miniature events when compared to vehicle control (blue) (n = 20 for each condition). (C) EPSC recordings obtained by applying a paired pulse facilitation protocol under control conditions (blue trace) and after Aβ oligomers perfusion (red trace). Inter pulse interval was 30 ms. Scale bars: horizontal, 20 ms; vertical 20 pA. (D) Quantification of the experiment shown in C. Perfusion of Aβ oligomers (red) does not affect paired-pulse facilitation when compared to control (blue). The response to the second pulse was normalized by the response to the first pulse (n = 10 for each condition). (E) Aβ induced synaptic depression is dependent on synaptic stimulation. Normalized EPSCs from CA1 neurons are shown. After baseline recordings, Aβ oligomers were added to the bath solution (black arrow) and the stimulation protocol paused for 10 minutes (represented by the black bar) before being resumed for another 10 min. (F) Quantification of the experiment shown in E. Bars indicate responses recorded during baseline (blue) and in presence of Aβ (red) at different time intervals: minute 12–13 averages responses recorded immediately after stimulation was resumed; minute 22–23 averages responses 10 minutes after stimulation was resumed (i.e. 19–20 minutes after the start of Aβ perfusion) (*p<0.05, n = 8).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672194&req=5

pone-0065350-g003: Aβ induced synaptic depression is dependent on synaptic stimulation.(A) Miniature EPSCs Upper traces: average of miniature events after perfusion of control (blue) or Aβ (red). Scale bars: horizontal, 5 ms; vertical 5 pA. Middle and lower traces: sample of a four seconds recording of miniature EPSC activity following perfusion of control (blue) or Aβ oligomers (red). Scale bars: horizontal 0.2 s; vertical 10 pA. (B) Perfusion of Aβ oligomers (red) does not change the amplitude (left) or the frequency (right) of recorded miniature events when compared to vehicle control (blue) (n = 20 for each condition). (C) EPSC recordings obtained by applying a paired pulse facilitation protocol under control conditions (blue trace) and after Aβ oligomers perfusion (red trace). Inter pulse interval was 30 ms. Scale bars: horizontal, 20 ms; vertical 20 pA. (D) Quantification of the experiment shown in C. Perfusion of Aβ oligomers (red) does not affect paired-pulse facilitation when compared to control (blue). The response to the second pulse was normalized by the response to the first pulse (n = 10 for each condition). (E) Aβ induced synaptic depression is dependent on synaptic stimulation. Normalized EPSCs from CA1 neurons are shown. After baseline recordings, Aβ oligomers were added to the bath solution (black arrow) and the stimulation protocol paused for 10 minutes (represented by the black bar) before being resumed for another 10 min. (F) Quantification of the experiment shown in E. Bars indicate responses recorded during baseline (blue) and in presence of Aβ (red) at different time intervals: minute 12–13 averages responses recorded immediately after stimulation was resumed; minute 22–23 averages responses 10 minutes after stimulation was resumed (i.e. 19–20 minutes after the start of Aβ perfusion) (*p<0.05, n = 8).
Mentions: To further characterize the basis of Aβ induced changes in synaptic transmission, we recorded synaptic miniature events in the presence of Aβ. We perfused slice cultures for 20 min with Aβ or vehicle, added TTX for 10 min and recorded miniature events (Fig. 3a). As seen in Figure 3b, we observed no changes in miniature amplitudes or frequency in the presence of Aβ and TTX. The unchanged miniature frequency is consistent with our data showing that Aβ does not affect fiber-volley amplitudes (Fig. 1b and c) or paired-pulse facilitation (Figure 3c and d), indicating that the presynaptic site is not involved in acute Aβ dependent synaptic depression. However, the lack of change in miniature amplitudes while having previously observed synaptic depression in field recordings (Fig. 1b) as well as whole-cell patch-clamp recordings (Fig. 2a), suggested that Aβ mediated synaptic depression is dependent on synaptic stimulation. To test this hypothesis, we repeated our experiment seen in Fig. 2a, but paused external stimulation during the first 10 min of Aβ perfusion. Resuming stimulation after 10 min Aβ perfusion revealed no synaptic depression for the first minutes, indicating that Aβ induced depression is dependent on synaptic stimulation. Consequently, 5 min after resuming stimulation, synaptic transmission became significantly reduced (Figure 3e and f; the steeper induction curve of depression in comparison to Fig. 2a is most likely due to Aβ already being present at the synapse when stimulation is resumed, i.e. slices are already perfused for 10 min with Aβ). Taken together, we conclude that Aβ can rapidly induce synaptic depression, but only in the presence of sufficient synaptic activity.

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