1S, 3R-ACPD induces a region of negative slope conductance in the steady-state current-voltage relationship of hippocampal pyramidal cells.

Synaptic responses mediated by metabotropic glutamate receptors (mGluRs) display a marked voltage-dependent increase in amplitude when neurons are moderately depolarized beyond membrane potential. We have investigated the basis for this apparent nonlinear behavior by activating mGluRs with 1S, 3R-1-aminocyclopentane-1, 3-dicarboxylate (1S, 3R-ACPD; 10 microM) in CA3 pyramidal cells from rat hippocampal slice cultures with the use of the single-electrode voltage-clamp technique. Under control conditions, cells depolarized from resting potential by 10-20 mV responded with delayed outwardly rectifying currents due to activation of voltage- and Ca(2+)-dependent K+ conductances. In contrast, in the continuous presence of 1S, 3R-ACPD, small depolarizations (10-20 mV) induced a delayed inward current. The steady-state current-voltage relationship for this response displayed a region of negative slope conductance at potentials between -55 and -40 mV. The reversal potential of the corresponding 1S,3R-ACPD-sensitive tail currents (-93.0 +/- 2.2 mV, mean +/- SE) was close to the potassium reversal potential, consistent with an mGluR-mediated suppression of K+ current. When external K+ concentration was increased to 8 mM, there was a positive shift in reversal potential to -76.9 +/- 5.1 mV. The depolarization-induced inward current in the presence of 1S,3R-ACPD was blocked by Ba2+ (1 mM). The response was not dependent on changes in intracellular Ca2+ concentration and was insensitive to bath-applied Cs+ (1 mM), ruling out a contribution of Ca(2+)-dependent currents or the inward rectifier lQ. Furthermore, the effect of 1S,3R-ACPD was not mimicked by inhibiting afterhyperpolarizing current and M current with low-Ca2+ saline (0.5 mM Ca2+, 10 mM Mg2+) containing 10 mM tetraethylammonium chloride. A comparison of the responses induced by 1S,3R-ACPD and N-methyl-D-aspartate showed that both induce an inward current with small depolarizations from resting potential but with different kinetics and Mg2+ sensitivity. These results indicate that the suppression of K+ currents in response to activation of mGluRs is markedly voltage dependent, increasing at depolarized potentials and decreasing at hyperpolarized potentials. The negative slope conductance at membrane voltages positive to resting potential may underlie the amplification of mGluR-mediated responses when the membrane potential approaches action potential threshold.