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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

Field Potential and Intracellular recording of CA1 pyramidal neurons after Wnt-5a treatment. (A, left), Superimposed, average (10 sweeps) of field potentials (fEPSPs) recorded from stratum radiatum of CA1 region before (a), after 30 min of Wnt-5a perfusion (b) and 20 min of washout (c). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in baseline and in presence of Wnt-5a (a+b). (A, middle), Time course of effect of Wnt-5a (black burbles) or Wnt-5a plus anti-Wnt-5a (white burbles) on fEPSPs peak amplitudes. Bottom, effect of Wnt-5a plus anti-Wnt-5a on fV. (B), Normalized amplitude of fEPSPs, evoked by the first stimulus (top), in control and after Wnt-5a or Wnt-5a plus anti-Wnt-5a treatment after 50 min of continued perfusion. Average values of normalized amplitude of fiber volley are shown (center), measured before (control) and after Wnt-5a (n = 6) or Wnt-5a plus Anti-Wnt-5a (n = 4) treatment application. Index of facilitation in both conditions (botton). (C, left), Superimposed, average EPSCs (20 sweeps) evoked by single stimulus and paired pulse stimulation at -90 and +40 mV of holding potential in control conditions (gray trace) and in the presence of Wnt-5a (black trace), respectively. (C, right) Summary data of average, normalized EPSCs amplitude and facilitation index, obtained in C in baseline and in the presence of Wnt-5a (n = 6), respectively. Bar represents the mean ± SEM (*p < 0.05 Student's t test).
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Figure 1: Field Potential and Intracellular recording of CA1 pyramidal neurons after Wnt-5a treatment. (A, left), Superimposed, average (10 sweeps) of field potentials (fEPSPs) recorded from stratum radiatum of CA1 region before (a), after 30 min of Wnt-5a perfusion (b) and 20 min of washout (c). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in baseline and in presence of Wnt-5a (a+b). (A, middle), Time course of effect of Wnt-5a (black burbles) or Wnt-5a plus anti-Wnt-5a (white burbles) on fEPSPs peak amplitudes. Bottom, effect of Wnt-5a plus anti-Wnt-5a on fV. (B), Normalized amplitude of fEPSPs, evoked by the first stimulus (top), in control and after Wnt-5a or Wnt-5a plus anti-Wnt-5a treatment after 50 min of continued perfusion. Average values of normalized amplitude of fiber volley are shown (center), measured before (control) and after Wnt-5a (n = 6) or Wnt-5a plus Anti-Wnt-5a (n = 4) treatment application. Index of facilitation in both conditions (botton). (C, left), Superimposed, average EPSCs (20 sweeps) evoked by single stimulus and paired pulse stimulation at -90 and +40 mV of holding potential in control conditions (gray trace) and in the presence of Wnt-5a (black trace), respectively. (C, right) Summary data of average, normalized EPSCs amplitude and facilitation index, obtained in C in baseline and in the presence of Wnt-5a (n = 6), respectively. Bar represents the mean ± SEM (*p < 0.05 Student's t test).

Mentions: To examine the effects of Wnt-5a on excitatory glutamatergic transmission evoked by stimulation of Schaffer collaterals (SC) in hippocampal slices, we recorded the field excitatory postsynaptic potentials (fEPSP) and the excitatory postsynaptic currents (EPSCs) in the presence of 10 μM picrotoxin (PTX) to block GABAA-mediated inhibitory synaptic transmission. The fEPSP amplitude increased after 20 min of Wnt-5a addition to Artificial CerebroSpinal Fluid (ACSF) perfusion media, 57.5% ± 15.5 (p < 0.05; n = 6), without changing either the fiber volley (fV) amplitude or paired pulse facilitation (PPF) (Figure 1A and 1B). This effect was antagonized completely in the presence of anti-Wnt-5a, a generic antibody again Wnt-5a domain [29], moreover, this Wnt-5a effect was reversible after 20 min of washout (Figure 1A and upper graphs)


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)

Field Potential and Intracellular recording of CA1 pyramidal neurons after Wnt-5a treatment. (A, left), Superimposed, average (10 sweeps) of field potentials (fEPSPs) recorded from stratum radiatum of CA1 region before (a), after 30 min of Wnt-5a perfusion (b) and 20 min of washout (c). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in baseline and in presence of Wnt-5a (a+b). (A, middle), Time course of effect of Wnt-5a (black burbles) or Wnt-5a plus anti-Wnt-5a (white burbles) on fEPSPs peak amplitudes. Bottom, effect of Wnt-5a plus anti-Wnt-5a on fV. (B), Normalized amplitude of fEPSPs, evoked by the first stimulus (top), in control and after Wnt-5a or Wnt-5a plus anti-Wnt-5a treatment after 50 min of continued perfusion. Average values of normalized amplitude of fiber volley are shown (center), measured before (control) and after Wnt-5a (n = 6) or Wnt-5a plus Anti-Wnt-5a (n = 4) treatment application. Index of facilitation in both conditions (botton). (C, left), Superimposed, average EPSCs (20 sweeps) evoked by single stimulus and paired pulse stimulation at -90 and +40 mV of holding potential in control conditions (gray trace) and in the presence of Wnt-5a (black trace), respectively. (C, right) Summary data of average, normalized EPSCs amplitude and facilitation index, obtained in C in baseline and in the presence of Wnt-5a (n = 6), respectively. 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 1: Field Potential and Intracellular recording of CA1 pyramidal neurons after Wnt-5a treatment. (A, left), Superimposed, average (10 sweeps) of field potentials (fEPSPs) recorded from stratum radiatum of CA1 region before (a), after 30 min of Wnt-5a perfusion (b) and 20 min of washout (c). (A, right), Superimposed, normalized (to R1), averaged (10 sweeps) fEPSPs evoked by paired pulse stimulation (100 ms delay) in baseline and in presence of Wnt-5a (a+b). (A, middle), Time course of effect of Wnt-5a (black burbles) or Wnt-5a plus anti-Wnt-5a (white burbles) on fEPSPs peak amplitudes. Bottom, effect of Wnt-5a plus anti-Wnt-5a on fV. (B), Normalized amplitude of fEPSPs, evoked by the first stimulus (top), in control and after Wnt-5a or Wnt-5a plus anti-Wnt-5a treatment after 50 min of continued perfusion. Average values of normalized amplitude of fiber volley are shown (center), measured before (control) and after Wnt-5a (n = 6) or Wnt-5a plus Anti-Wnt-5a (n = 4) treatment application. Index of facilitation in both conditions (botton). (C, left), Superimposed, average EPSCs (20 sweeps) evoked by single stimulus and paired pulse stimulation at -90 and +40 mV of holding potential in control conditions (gray trace) and in the presence of Wnt-5a (black trace), respectively. (C, right) Summary data of average, normalized EPSCs amplitude and facilitation index, obtained in C in baseline and in the presence of Wnt-5a (n = 6), respectively. Bar represents the mean ± SEM (*p < 0.05 Student's t test).
Mentions: To examine the effects of Wnt-5a on excitatory glutamatergic transmission evoked by stimulation of Schaffer collaterals (SC) in hippocampal slices, we recorded the field excitatory postsynaptic potentials (fEPSP) and the excitatory postsynaptic currents (EPSCs) in the presence of 10 μM picrotoxin (PTX) to block GABAA-mediated inhibitory synaptic transmission. The fEPSP amplitude increased after 20 min of Wnt-5a addition to Artificial CerebroSpinal Fluid (ACSF) perfusion media, 57.5% ± 15.5 (p < 0.05; n = 6), without changing either the fiber volley (fV) amplitude or paired pulse facilitation (PPF) (Figure 1A and 1B). This effect was antagonized completely in the presence of anti-Wnt-5a, a generic antibody again Wnt-5a domain [29], moreover, this Wnt-5a effect was reversible after 20 min of washout (Figure 1A and upper graphs)

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