Figure 6
Compensatory increases in glycine/GABA A receptor-mediated input fail to prevent disinhibition if reduction of E anion exceeds a critical value. (A) Under normal conditions, E anion = -70 mV. Inhibition with α = 0.5 compresses the f out-f exc curve as shown by the white arrow, producing an f out/f out0 ratio of approximately 0.6. Reduction of the f out/f out0 ratio to 0.6 represents a conservative estimate of inhibition; higher values of α result in greater compression of the f out-f exc curve and lower f out/f out0 ratios. Using this conservative estimate for illustrative purposes, f out/f out0 > 0.6 (pink region) represents disinhibition while f out/f out0 > 1 (red region) represents paradoxical excitation. (B) If E anion is reduced to -60 mV, inhibition with α = 0.5 does not reduce f out as much as it did with E anion = -70 mV; the resulting f out-f exc curve falls inside the pink region, indicative of disinhibition. But if α is increased to 1.2 (blue curve), the f out-f exc curve is returned to the white-pink border, meaning f out/f out0 ≈ 0.6. This demonstrates that disinhibition caused by moderate reduction of E anion is compensable. (C) If E anion is reduced to -55 mV, increasing α as high as 2 still fails to shift the f out-f exc curve outside the pink region, demonstrating that disinhibition caused by larger reduction of E anion becomes incompensable. (D) If E anion is reduced to -50 mV, increasing α actually shifts the f out-f exc curve into the red region, demonstrating that even larger reductions of E anion can result in paradoxical excitation. (E) Contour plot show combinations of E anion and α that produce disinhibition (f out/f out0 > 0.6, demarcated by pink line) and paradoxical excitation (f out/f out0 > 1, demarcated by red line) calculated for f exc = 80 Hz. Arrowheads mark E anion at which decompensation occurs, assuming α could increase as high as 4. (F) These graphs show cross-sections through the contour plots in part E. Increasing α to 4 prevents disinhibition from occurring until E anion reduces to -54 mV, but steepening of the curve means that decompensation occurs abruptly (e.g. reduction of E anion from -55 to -50 mV causes f out/f out0 to nearly triple, increasing from 0.47 to 1.28) whereas disinhibition develops more gradually in the absence of compensation (e.g. with α = 0.5, the same change in E anion causes f out/f out0 to change from 1.01 to 1.13).