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. 2018 Feb 14;4:89–102. doi: 10.1016/j.trci.2018.01.002

Fig. 2.

Fig. 2

Inhibiting PLD activity prevents the synaptic dysfunction driven by oAβ in the Schaffer collateral synapses in the WT mouse hippocampus. fEPSPs were evaluated following standard HFS protocol (3 × 100 Hz) depicted by three arrows in (B) and (C) and compared to the baseline and plotted as a percentage of the original value (A–C). Applications of the oligomers follow the schematic depicted in the gray box above the graphs. Representative traces are provided next to the bars or symbols, with the length of the vertical scale bar at 0.5 mV and the horizontal scale bar at 10 ms. The application of the inhibitor was started 15 minutes before the application of the oligomers and continued through the time that the slices were incubated with the oligomers. (A) As the oAβ concentration increased from 20 nM to 2 μM, the HFS LTP (last 10 minutes) decreased from ∼280% to ∼100% (clear bars—20 nM oAβ: 281.20 ± 8.515, n = 12; 200 nM oAβ: 176.10 ± 6.798, n = 24; and 2-μM oAβ: 98.09 ± 5.730, n = 12). Both PLD1-specific inhibitor (VU0155069, filled squares) and PLD2-specific inhibitor (VU0364739, filled triangles) were ineffective in suppressing the LTP effect of 200 nM oAβ at the lowest concentration tested (2 nM PLD1 inhibitor: 163.2 ± 5.509, n = 6 and 2 nM PLD2 inhibitor: 182.0 ± 6.137, n = 6) but could prevent the oAβ-driven LTP deficit at higher concentrations (20 nM PLD1 inhibitor: 265.7 ± 5.590, n = 6; 20 nM PLD2 inhibitor: 246.5 ± 6.724, n = 6; 200 nM PLD1 inhibitor: 268.7 ± 7.183, n = 6; and 200 nM PLD2 inhibitor: 299.9 ± 6.618, n = 6, *P < .05). (B) PLD1 inhibitor at 20 nM (inverted hollow triangles) and 200 nM (filled circles) shows complete recovery of the Schaffer collateral HFS LTP including PTP (first 10 minutes) and LTP (last 10 minutes), whereas the inhibitor at 2 nM (hollow hexagons) is ineffective in overcoming effect of oAβ inhibition (200 nM, hollow squares). (C) The PLD2 inhibitor at the highest concentration tested (200 nM, filled circles) completely attenuates the LTP deficits seen with oAβ (200 nM, hollow squares), whereas it is completely ineffective at 2 nM (hollow hexagons), with some recovery of PTP, but not LTP. At the intermediate concentration of 20 nM (inverted triangles), the PLD2 inhibitor shows an intermediate recovery of the LTP that is significantly higher than 2 nM, but lower than 200 nM. Statistical significance was assessed using nonparametric one-way ANOVA (Kruskal-Wallis test) followed by Dunn's multiple comparison. Abbreviations: Aβ, amyloid β; ANOVA, analysis of variance; fEPSP, field excitatory postsynaptic potential; HFS, high-frequency stimulation; Inh, inhibitor; LTP, long-term potentiation; oAβ, oligomeric Aβ; PLD, phospholipase D; PLD1, phospholipase D isoform 1; PLD2, phospholipase D isoform 2; PTP, posttetanic potentiation; WT, wild-type.