Figure 6.
Compensatory increases in glycine/GABAA receptor-mediated input fail to prevent disinhibition if reduction of Eanion exceeds a critical value. (A) Under normal conditions, Eanion = -70 mV. Inhibition with α = 0.5 compresses the fout-fexc curve as shown by the white arrow, producing an fout/fout0 ratio of approximately 0.6. Reduction of the fout/fout0 ratio to 0.6 represents a conservative estimate of inhibition; higher values of α result in greater compression of the fout-fexc curve and lower fout/fout0 ratios. Using this conservative estimate for illustrative purposes, fout/fout0 > 0.6 (pink region) represents disinhibition while fout/fout0 > 1 (red region) represents paradoxical excitation. (B) If Eanion is reduced to -60 mV, inhibition with α = 0.5 does not reduce fout as much as it did with Eanion = -70 mV; the resulting fout-fexc curve falls inside the pink region, indicative of disinhibition. But if α is increased to 1.2 (blue curve), the fout-fexc curve is returned to the white-pink border, meaning fout/fout0 ≈ 0.6. This demonstrates that disinhibition caused by moderate reduction of Eanion is compensable. (C) If Eanion is reduced to -55 mV, increasing α as high as 2 still fails to shift the fout-fexc curve outside the pink region, demonstrating that disinhibition caused by larger reduction of Eanion becomes incompensable. (D) If Eanion is reduced to -50 mV, increasing α actually shifts the fout-fexc curve into the red region, demonstrating that even larger reductions of Eanion can result in paradoxical excitation. (E) Contour plot show combinations of Eanion and α that produce disinhibition (fout/fout0 > 0.6, demarcated by pink line) and paradoxical excitation (fout/fout0 > 1, demarcated by red line) calculated for fexc = 80 Hz. Arrowheads mark Eanion 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 Eanion reduces to -54 mV, but steepening of the curve means that decompensation occurs abruptly (e.g. reduction of Eanion from -55 to -50 mV causes fout/fout0 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 Eanion causes fout/fout0 to change from 1.01 to 1.13).