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Properties of single NMDA receptor channels in human dentate gyrus granule cells

David N. Lieberman and Istvan Mody *

Cell-attached single-channel recordings of NMDA channels were carried out in human dentate gyrus granule cells acutely dissociated from slices prepared from hippocampi surgically removed for the treatment of temporal lobe epilepsy (TLE). The channels were activated by L-aspartate (250-500 nM) in the presence of saturating glycine (8 µM).

The main conductance was 51 ± 3 pS. In ten of thirty granule cells, clear subconductance states were observed with a mean conductance of 42 ± 3 pS, representing 8 ± 2 % of the total openings.

The mean open times varied from cell to cell, possibly owing to differences in the epileptogenicity of the tissue of origin. The mean open time was 2·70 ± 0·95 ms (range, 1·24-4·78 ms). In 87 % of the cells, three exponential components were required to fit the apparent open time distributions. In the remaining neurons, as in control rat granule cells, two exponentials were sufficient. Shut time distributions were fitted by five exponential components.

The average numbers of openings in bursts (1·74 ± 0·09) and clusters (3·06 ± 0·26) were similar to values obtained in rodents. The mean burst (6·66 ± 0·9 ms), cluster (20·1 ± 3·3 ms) and supercluster lengths (116·7 ± 17·5 ms) were longer than those in control rat granule cells, but approached the values previously reported for TLE (kindled) rats.

As in rat NMDA channels, adjacent open and shut intervals appeared to be inversely related to each other, but it was only the relative areas of the three open time constants that changed with adjacent shut time intervals.

The long openings of human TLE NMDA channels resembled those produced by calcineurin inhibitors in control rat granule cells. Yet the calcineurin inhibitor FK-506 (500 nM) did not prolong the openings of human channels, consistent with a decreased calcineurin activity in human TLE.

Many properties of the human NMDA channels resemble those recorded in rat hippocampal neurons. Both have similar slope conductances, five exponential shut time distributions, complex groupings of openings, and a comparable number of openings per grouping. Other properties of human TLE NMDA channels correspond to those observed in kindling; the openings are considerably long, requiring an additional exponential component to fit their distributions, and inhibition of calcineurin is without effect in prolonging the openings.

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