Opponent effects of potassium on GABA(A)-mediated postsynaptic inhibition in the rat hippocampus

1. The effects of raising the concentration of extracellular potassium ([K⁺](o)) on γ-aminobutyric acid (GABA)-mediated inhibitory postsynaptic potentials (IPSPs) were investigated in adult rat hippocampal slices using intracellular recording techniques. IPSPs were evoked in CA1 pyramidal neurons by direct activation of inhibitory interneurons in slices treated with glutamatergic antagonists to block excitatory synaptic transmission. The fast (Cl^--dependent, GABA(A) receptor-mediated) IPSPs (fIPSPs) were isolated from the slow (K⁺-dependent; GABA(B) receptor-mediated) IPSPs (sIPSPs) by intracellular injection of QX-314, which also suppressed fast (Na⁺- dependent) action potentials. 2. In normal (3.5 mM) and in high (7.5 mM) [K⁺](o), the peak fIPSP amplitude changed nonlinearly with membrane potential (V(M)) in a way consistent with outward rectification of the underlying conductance. The input conductance of the fIPSP (G(fIPSP)) measured around resting V(M) (about -67 mV) increased 1.7-fold on changing from normal to high-K⁺ saline, whereas resting V(M) depolarized 6.8 mV. Repolarizing V(M) reversed the increase in G(fIPSP), suggesting that it was due to outward rectification. The resting input conductance of the neurons increased 1.4-fold in high K⁺. 3. The time course of fIPSPs was prolonged by high K⁺. The half time of fIPSP decay increased 1.4-fold, and in half of the neurons the decay became conspicuously multipeaked, suggesting that neurally evoked GABA release from inhibitory interneurons was prolonged. 4. In normal K⁺, the reversal potentials of fIPSPs (E(fIPSP); -76.5 mV) was 9.7 mV more negative than resting V(M). Polarizing V(M) 10-20 mV for 15 min with current injection did not change E(fIPSP) appreciably. Changing to high-K⁺ saline reduced E(fIPSP) by 10.9 mV. Maintaining a steady V(M) with current injection did not prevent the decrease in E(fIPSP), indicating that [K⁺](o) modulates E(fIPSP) directly. Likewise, polarizing V(M) in high-K⁺ saline did not change E(fIPSP) > 1-2 mV. 5. sIPSPs conjointly activated with fIPSPs (in the absence of QX-314) had a reversal potential (E(sIPSP)) of -96.4 mV in normal [K⁺](o) that decreased 16 mV in 7.5 mM [K⁺](o). E(fIPSP) and E(sIPSP) changed simultaneously during the washin and washout of high-K⁺ saline, indicating that intracellular Cl^- concentration accomodates rapidly to [K⁺](o) perturbations. 6. All effects of high K⁺ on membrane properties and IPSPs reversed on wash with normal saline. 7. We conclude that increased [K⁺](o) exerts opponent effects on fast inhibitory synaptic transmission in the hippocampus. It secondarily augments and prolongs G(fIPSP) while reducing E(fIPSP). The concurrence of these effects may attenuate changes in the efficacy of GABA(A)-mediated inhibition consequent to physiological and pathophysiological increases of [K⁺](o).