Reduced Mg 2+ blockade of synaptically activated N-methyl- d-aspartate receptor-channels in CA1 pyramidal neurons in kainic acid-lesioned rat hippocampus

Abstract

Unilateral kainic acid lesion in the hippocampus caused a long-term change in the balance between excitatory and inhibitory drive onto CA1 pyramidal cells, making these cells hyperexcitable several weeks post-lesion. In this study, we have shown an enhanced N-methyl- d-aspartate receptor-mediated component in the excitatory synaptic transmission together with a reduced GABA A receptor-mediated inhibition in CA1 pyramidal cells one-week post kainic acid lesion. In these cells, pharmacologically isolated N-methyl- d-aspartate receptor-mediated whole-cell excitatory postsynaptic currents were significantly larger at negative holding potentials, and the voltage-dependence of N-methyl- d-aspartate receptor channels was shifted in the hyperpolarizing direction. The plot of relative conductance (g/g Max) shifted significantly ( P<0.01) to more negative holding potentials by 19 mV (−28±4 mV in control slices and −47±4 mV in kainic acid slices) at the half maximal conductance point (g/g Max=0.5). This shift gives a larger N-methyl- d-aspartate receptor-mediated component in the excitatory synaptic transmission at resting membrane potentials (around −60 mV). The shifted voltage dependence is highly sensitive to extracellular Mg 2+ ions. Moderate increases in [Mg 2+] o from 1 mM to 2.6 mM more than compensated for the negative shift and effectively suppressed the population epileptiform bursting activity. Fitting the voltage dependence to an ionic block model revealed a higher dissociation constant of N-methyl- d-aspartate receptor channels for Mg 2+ in kainic acid-lesioned slices (52 mM at 0 mV; 330 μM at −60 mV) than in control slices (7.7 mM at 0 mV; 93 μM at −60 mV). While a simple single site model adequately fitted the control data for [Mg 2+] o at 1 mM and 2.6 mM, no consistent model of this form was found for the kainic acid-lesioned slices. These results revealed changed properties of N-methyl- d-aspartate receptor channels in the kainic acid-lesioned model of epilepsy. The reduced Mg 2+ blockade of N-methyl- d-aspartate receptor channels contributed significantly to the epileptiform bursting activity.