Figure 8
Therapeutically correcting E anion -mediated disinhibition by augmenting GABAergic input risks introducing instability into the system, and suggests that other therapeutic interventions may be preferable. The f out/f out0 ratio is calculated for f exc = 80 Hz. (A) Doubling w and τdecay of GABAA receptor-mediated input, as might occur with benzodiazepines, increased the value of E anion at which decompensation occurred (where curve enters pink region indicating f out/f out0 > 0.6), but it risked exacerbating paradoxical excitation if reduction of E anion was large. Increasing GABAergic transmission had effects comparable to increasing α (compare with Fig. 6F): with α = 0.5 (dotted curve), increasing GABA approximated effects of increasing α to 1.2 (i.e. increase of 0.7 or 2.4×) while with α = 2 (dashed curve), increasing GABA approximated effects of increasing α to 4.4 (i.e. increase of 2.4 or 2.2×). This demonstrates that strength and frequency of input interact multiplicatively. (B) Unlike modulating inhibitory input, blocking NMDA receptor-mediated excitation shifted the curve relating f out/f out0 and f exc. (C) Combining NMDA antagonism with increased GABAergic transmission had purely additive effects. Augmenting inhibitory input alone or in combination with reducing excitatory input can prevent decompensation until the reduction in E anion becomes larger than that necessary to produce decompensation without an increase in inhibition. However, there are several complications: 1) decompensation still occurs for large reduction in E anion; 2) the balance achieved by increasing inhibition is unstable inasmuch as the curve is steep when passing through f out/f out0 = 0.6 meaning small changes in E anion can cause abrupt decompensation; and 3) for neurons that maintain E anion = -70 mV, exposure to a benzodiazepine will reduce f out/f out0 significantly below 0.6. (D) One possible solution to these problems is to deliberately block inhibition (upward arrow in graph on right) and counterbalance the consequent increase f out/f out0 by a titrated reduction in excitation (downward arrow). For simulations shown here, GABA, glycine, and NMDA receptor-mediated input were blocked and AMPA receptor-mediated input was decreased until an f out/f out0 ratio of ~0.6 was achieved. By removing inhibition, the f out/f out0 ratio becomes insensitive to E anion and α, meaning f out/f out0 remains stable despite changes in either variable and, furthermore, variation in E anion and α between affected and unaffected cells does not influence f out/f out0.