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Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of <t>NS309</t> in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).
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Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of <t>NS309</t> in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).
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Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of <t>NS309</t> in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).
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Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of <t>NS309</t> in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).
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Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of <t>NS309</t> in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).
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Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of <t>NS309</t> in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).
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Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of NS309 in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).

Journal: iScience

Article Title: Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant

doi: 10.1016/j.isci.2025.114301

Figure Lengend Snippet: Potentiating SK channels restores normal NMDAR integration in Grin1 Y647S +/− mice (A) Schematic of potential mechanism showing impaired negative feedback in Y647S +/− neurons due to insufficient Ca 2+ influx compared to WT and the effect of NS309 in boosting SK channel Ca 2+ sensitivity, thereby restoring negative feedback in Y647S +/− neurons. (B) Average NMDAR plateau potential in Y647S +/− neurons at 70 μA with extended tail indicated by red arrow. Application of 10 μM NS309 to the slice restores normal duration and terminates the NMDAR plateau potential in Y647S +/− (Y647S +/− + NS309). (Inset) Restoration of plateau potential duration by NS309 at increasing stimulus intensities in a Y647S +/− neuron. (C) Total width of the NMDAR plateau potential in WT, Y647S +/− , and Y647S +/− + NS309 neurons (∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 10 −4 , Tukey’s post hoc. Black stars: WT vs. Y647S +/− , purple stars: Y647S +/− vs. Y647S +/− + NS309). (D) SK2 channel blocker (Leidab7, 100 nM) prevents NS309 from reducing plateau potential duration in Y647S +/− neurons. (E) Normalized NMDAR plateau width in Y647S +/− neurons with the addition of NS309 and NS309+SK2 blockers (∗ p < 0.05, Sidak’s post hoc).

Article Snippet: SK channel positive allosteric modulator NS309 (10 μM, Tocris ) was included in a subset of experiments to restore appropriate duration of dendritic integration in Y647S +/− mice.

Techniques: