PROPERTIES OF NMDA RECEPTOR CHANNELS IN NEURONS ACUTELY ISOLATED FROMEPILEPTIC (KINDLED) RATS

The hyperexcitability accompanying chronic epileptiform activity may r esult from long-term alterations of ligand- and voltage-gated channels . Previous studies have indicated that NMDA responses and other electr ophysiological characteristics of dentate gyrus granule cells are prof oundly altered following chronic epilepsy (kindling). We have now inve stigated channels activated by NMDA using whole-cell patch-clamp and c ell-attached single-channel recordings in granule cells acutely isolat ed from control and epileptic (kindled) rats. In control neurons, the amplitude of whole-cell NMDA currents was not sensitive to the presenc e of an intracellular ATP regeneration system, whereas NMDA currents i n kindled cells showed a great variability, with larger amplitudes con sistently recorded in the presence of intracellular high-energy phosph ates. The ratio of peak to steady-state NMDA current (desensitization) was comparable (almost-equal-to 51 %) in control and kindled neurons. Single-channel conductance determined from fluctuation analysis of wh ole-cell NMDA currents ranged between 21 and 35 pS in control and betw een 17 and 37 pS in kindled cells. Whole-cell NMDA channel noise power spectra yielded a single normal distribution of long channel lifetime s (mean, 4.3 msec) in control neurons, and the sum of two normal distr ibutions (means, 4.6 and 7.1 msec) in kindled cells. The voltage-depen dent Mg2+ block of NMDA channels was altered following kindling. From curves fitted to voltage-ramp-evoked currents in the presence of NMDA, the calculated affinity for Mg2+ of kindled channels at 0 mV was lowe r (12 mm) than that of controls (1.7 mm). Cell-attached recordings in the absence of Mg2+ have substantiated the lack of effect of kindling on single-channel conductance (almost-equal-to 50 pS), and have demons trated large increases in mean open times (from 1.26 msec in control t o 2.05 msec in kindled), burst lengths (from 1.91 msec to 4. 1 8 msec) , and cluster lengths (from 9.11 msec to 20.86 msec) of NMDA channels in kindled neurons. In summary, kindling, an NMDA receptor-dependent f orm of activity-dependent neuronal plasticity induced in vivo, results in lasting modifications in the function of single NMDA receptor chan nels that can be studied in acutely dissociated neurons. Kindling-indu ced epilepsy predominantly affects the mean open time, burst, and clus ter duration of NMDA channels, their sensitivity to intracellular high -energy phosphates, and their block by Mg2+, but not the desensitizati on or single-channel conductance. Such alterations may reflect a chang e in the molecular structure of NMDA channels and may underlie the mai ntenance of the epileptic state.