PHYSIOLOGICAL UNMASKING OF NEW GLUTAMATERGIC PATHWAYS IN THE DENTATE GYRUS OF HIPPOCAMPAL SLICES FROM KAINATE-INDUCED EPILEPTIC RATS

Physiological unmasking of new glutamatergic pathways in the dentate g yrus of hippocampal slices from kainate-induced epileptic rats. J. Neu rophysiol. 79: 418-429, 1998. In humans with temporal lobe epilepsy an d kainate-treated rats, the mossy fibers of the dentate granule cells send collateral axons into the inner molecular layer. Prior investigat ions on kainate;treated rats demonstrated that abnormal hilar-evoked e vents can occasionally be observed in slices with mossy fiber sproutin g when gamma-aminobutyric acid-A (GABA(A))-mediated inhibition is bloc ked with bicuculline. However, these abnormalities were observed infre quently, and it was unknown whether these rats were epileptic. Wuarin and Dudek reported that in slices from kainate-induced epileptic rats (3-13 mo after treatment), hilar stimulation evoked abnormal events in most slices with mossy fiber sprouting exposed simultaneously to bicu culline and elevated extracellular potassium concentration [K+](0). Us ing the same rats, extracellular recordings were obtained from granule cells In hippocampal slices to determine whether 1) hilar stimulation could evoke abnormal events in slices with sprouting in normal artifi cial cerebrospinal fluid (ACSF), 2) adding only bicuculline could unma sk hilar-evoked abnormalities and glutamate-receptor antagonists could block these events, and 3) increasing only [K+](o), could unmask thes e abnormalities. In normal ACSF, hilar stimulation evoked abnormal fie ld potentials in 27% of slices with sprouting versus controls without sprouting (i.e., saline-heated or only 2-4 days after kainate treatmen t). In bicuculline (10 mu M) alone, hilar stimulation triggered prolon ged field potentials in 84% of slices with sprouting, but not in slice s from the two control groups. Addition of the N-methyl-D-aspartate (N MDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5), either blocked the bursts or reduced their probability of occurrence. The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kaina te receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), alway s eliminated the epileptiform bursts. In kainate-treated rats with spr outing, but not in saline-treated controls, abnormal hilar-evoked resp onses were also revealed in 6-9 mM [K+](o). Additionally, 63% of slice s with sprouting generated spontaneous bursts lasting 1-40 s in ACSF c ontaining 9 mm [K+](o); similar bursts were not observed in controls. These results indicate that I) mossy fiber sprouting is associated wit h new glutamatergic pathways, and although NMDA receptors are importan t for propagation through these circuits, AMPA receptor activation is crucial, 2) modest elevations of [K+](o), in a range that would have r elatively little effect on granule cells, can unmask these new excitat ory circuits and generate epileptiform bursts, and 3) this new circuit ry underlies an increased electrographic seizure susceptibility when i nhibition is depressed or membrane excitability is increased.