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Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

Cerpa W, Farías GG, Godoy JA, Fuenzalida M, Bonansco C, Inestrosa NC - Mol Neurodegener (2010)

Bottom Line: Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well.Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures.Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología "Joaquín V, Luco" (CRCP), MIFAB, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. ninestrosa@bio.puc.cl.

ABSTRACT

Background: Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.

Results: We report here that the Wnt signaling activation prevents the synaptic damage triggered by Abeta oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

Conclusion: These results indicate that post-synaptic damage induced by Abeta oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

No MeSH data available.


Related in: MedlinePlus

Aβ oligomers decrease mainly the NMDA current. (A) Average (20 sweeps) EPSCs in control (left), after treatment with CNQX (gray trace) or CNQX plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential obtained from a same neuron. B) Average (20 sweeps) EPSCs in control (left), after treatment with APV (gray trace) or APV plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential. C) Summary data of normalized amplitude (to control) of evoked EPSCs obtained from experiments on A (n = 6) and B (n = 5). Bar represents the mean ± SEM (*p < 0.05 Student's t test).
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Figure 3: Aβ oligomers decrease mainly the NMDA current. (A) Average (20 sweeps) EPSCs in control (left), after treatment with CNQX (gray trace) or CNQX plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential obtained from a same neuron. B) Average (20 sweeps) EPSCs in control (left), after treatment with APV (gray trace) or APV plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential. C) Summary data of normalized amplitude (to control) of evoked EPSCs obtained from experiments on A (n = 6) and B (n = 5). Bar represents the mean ± SEM (*p < 0.05 Student's t test).

Mentions: Previous evidence has shown that removal of AMPARs is necessary and sufficient to induce the Aβ-mediated synaptic depression [31]. To test whether NMDARs and AMPARs showed different sensitivities to Aβ oligomers, we compared their effects on SC (Shaffer Collaterals) evoked current by clampling the neuron at both +40 and -80 mV, in the presence of the glutamate receptor antagonists DL-2-amino-5-phosphonovaleric acid (50 μM APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (20 μM CNQX), respectively. In the presence of CNQX, the EPSCs at -80 mV were completely abolished, while at +40 mV were reduced until a 65% respect to control ASCF (Figure 3A). Under these conditions, perfusion of 500 nM Aβ oligomers decreased the NMDARs-mediated-response, reaching only 27% of the control EPSC ASCF amplitude. In the presence of APV, the EPSCs amplitude and decay constants (data non shown), measured at both -80 and +40 mV holding potentials were diminished with respect to control ASCF (Figure 3B). The addition of Aβ oligomers reduced the AMPARs-mediated-response reaching only 75% of the EPSC control ASCF amplitude. On average, in the presence of Aβ oligomers the mean values of EPSCs responses mediated by NMDARs (i.e.: CNQX and +40 mV; n = 6) were significantly lower than AMPARs (i.e.: APV and -80 mV; n = 5 neurons) (Figure 3C). The above results show that the synaptic depression induced by Aβ oligomers affects the NMDAR more than the AMPAR receptors.


Wnt-5a occludes Abeta oligomer-induced depression of glutamatergic transmission in hippocampal neurons.

Cerpa W, Farías GG, Godoy JA, Fuenzalida M, Bonansco C, Inestrosa NC - Mol Neurodegener (2010)

Aβ oligomers decrease mainly the NMDA current. (A) Average (20 sweeps) EPSCs in control (left), after treatment with CNQX (gray trace) or CNQX plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential obtained from a same neuron. B) Average (20 sweeps) EPSCs in control (left), after treatment with APV (gray trace) or APV plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential. C) Summary data of normalized amplitude (to control) of evoked EPSCs obtained from experiments on A (n = 6) and B (n = 5). Bar represents the mean ± SEM (*p < 0.05 Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2823745&req=5

Figure 3: Aβ oligomers decrease mainly the NMDA current. (A) Average (20 sweeps) EPSCs in control (left), after treatment with CNQX (gray trace) or CNQX plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential obtained from a same neuron. B) Average (20 sweeps) EPSCs in control (left), after treatment with APV (gray trace) or APV plus Aβ oligomers (black trace) (right) at -80 and +40 mV of holding potential. C) Summary data of normalized amplitude (to control) of evoked EPSCs obtained from experiments on A (n = 6) and B (n = 5). Bar represents the mean ± SEM (*p < 0.05 Student's t test).
Mentions: Previous evidence has shown that removal of AMPARs is necessary and sufficient to induce the Aβ-mediated synaptic depression [31]. To test whether NMDARs and AMPARs showed different sensitivities to Aβ oligomers, we compared their effects on SC (Shaffer Collaterals) evoked current by clampling the neuron at both +40 and -80 mV, in the presence of the glutamate receptor antagonists DL-2-amino-5-phosphonovaleric acid (50 μM APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (20 μM CNQX), respectively. In the presence of CNQX, the EPSCs at -80 mV were completely abolished, while at +40 mV were reduced until a 65% respect to control ASCF (Figure 3A). Under these conditions, perfusion of 500 nM Aβ oligomers decreased the NMDARs-mediated-response, reaching only 27% of the control EPSC ASCF amplitude. In the presence of APV, the EPSCs amplitude and decay constants (data non shown), measured at both -80 and +40 mV holding potentials were diminished with respect to control ASCF (Figure 3B). The addition of Aβ oligomers reduced the AMPARs-mediated-response reaching only 75% of the EPSC control ASCF amplitude. On average, in the presence of Aβ oligomers the mean values of EPSCs responses mediated by NMDARs (i.e.: CNQX and +40 mV; n = 6) were significantly lower than AMPARs (i.e.: APV and -80 mV; n = 5 neurons) (Figure 3C). The above results show that the synaptic depression induced by Aβ oligomers affects the NMDAR more than the AMPAR receptors.

Bottom Line: Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well.Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures.Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología "Joaquín V, Luco" (CRCP), MIFAB, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. ninestrosa@bio.puc.cl.

ABSTRACT

Background: Soluble amyloid-beta (Abeta;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Abeta oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.

Results: We report here that the Wnt signaling activation prevents the synaptic damage triggered by Abeta oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Abeta oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Abeta oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Abeta oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Abeta oligomers inversely modulate postsynaptic components.

Conclusion: These results indicate that post-synaptic damage induced by Abeta oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

No MeSH data available.


Related in: MedlinePlus