Figure 8.
Therapeutically correcting Eanion-mediated disinhibition by augmenting GABAergic input risks introducing instability into the system, and suggests that other therapeutic interventions may be preferable. The fout/fout0 ratio is calculated for fexc = 80 Hz. (A) Doubling w and τdecay of GABAA receptor-mediated input, as might occur with benzodiazepines, increased the value of Eanion at which decompensation occurred (where curve enters pink region indicating fout/fout0 > 0.6), but it risked exacerbating paradoxical excitation if reduction of Eanion 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 fout/fout0 and fexc. (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 Eanion 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 Eanion; 2) the balance achieved by increasing inhibition is unstable inasmuch as the curve is steep when passing through fout/fout0 = 0.6 meaning small changes in Eanion can cause abrupt decompensation; and 3) for neurons that maintain Eanion = -70 mV, exposure to a benzodiazepine will reduce fout/fout0 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 fout/fout0 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 fout/fout0 ratio of ~0.6 was achieved. By removing inhibition, the fout/fout0 ratio becomes insensitive to Eanion and α, meaning fout/fout0 remains stable despite changes in either variable and, furthermore, variation in Eanion and α between affected and unaffected cells does not influence fout/fout0.