HIPPOCAMPAL INHIBITORY NEURON ACTIVITY IN THE ELEVATED POTASSIUM MODEL OF EPILEPSY

1. Whole cell patch-clamp recordings were made from CA1 stratum oriens inhibitory neurons of rat hippocampal slices in vitro to determine th eir contribution to the epileptiform activity elicited by elevating th e extracellular potassium ion concentration ([K+](o)) from 3.5 to 8.5 mm. 2. Under current-clamp conditions, spontaneous action potential ac tivity in inhibitory neurons normally occurs in a sustained repetitive firing mode paced by nonsynaptic, intrinsic mechanisms. On elevation of [K+](o) to 8.5 mm the pattern of activity is altered such that clus ters of action potentials occur interrupted by periods of silence with out an appreciable afterhyperpolarization (AHP). In addition, elevatio n of [K+](o) caused a large reduction in the action potential AHP ampl itude and duration concomitant with a 20-mV shift in the reversal pote ntial of the AHP. 3. In voltage clamp a small persistent inward curren t was observed after the introduction of elevated potassium concomitan t with an increase in the frequency of spontaneous excitatory postsyna ptic currents (EPSCs) in all interneurons studied. After a short perio d of time (similar to 1 min) temporal summation of synchronously occur ring EPSCs contributed a periodic inward current (PIC; 10-40 pA, 0.8 H z) that persisted for the duration of the [K+](o) elevation. Analysis of the charge transfer associated with the PIC suggests that they comp rise the temporal summation of similar to 35 EPSCs. This PIC was synch ronous with the extracellular field potential recorded from the CA1 py ramidal neuron layer. 4. The PIC was responsible for the clustering of action potential activity because blockade of EPSC activity by the lp ha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) abolished PICs and reverted action potential activity to single sustained firing, despite the continued application of 8.5 mm [K+](o). Antagonists of N-methyl- D-aspartate receptors were without effect on either the PICs or the ac tion potential activity. 5. Addition of the metabotropic glutamate rec eptor (mGluR) antagonist (+)-2-methyl-4-carboxyphenylglycine (MCPG) re versibly abolished the PIC without affecting the increase in EPSC freq uency. 6. Recordings from CA3 pyramidal neurons in 8.5 mm [K+](o) demo nstrated that interictal activity occurred at a frequency identical to the PICs observed in interneurons. Interictal activity in CA3 pyramid al neurons was attenuated but never abolished by MCPG, suggesting a ro le for mGluR receptors in the maintenance of interictal activity in ar ea CA3. 7. Flurries of synchronous inhibitory postsynaptic currents (I PSCs) were observed on a small number of CA1 pyramidal neurons on elev ation of [K+]o, consistent with these neurons being the synaptic targe t of stratum oriens/alveus interneurons. Unexpectedly, a rundown of th is IPSC activity was observed during the transition to CA1 pyramidal n euron epileptiform activity. 8. In CA1 pyramidal neurons, current-volt age relationships measured at the peak response to gamma-aminobutyric acid (GABA) were identical in both normal or elevated [K+](o). However , subsequent current-voltage relationships determined during the fade of the GABA response revealed a positive shift in the reversal potenti al in both control and 8.5 mm [K+](o) conditions. The mechanism for th is positive shift in reversal potential is at present un known but may occur due to the intracellular accumulation of Cl- after sustained GA BA receptor activation. 9. These experiments suggest that the ongoing intrinsic action potential activity of the CA1 interneuron population is ''overridden'' during electrographic activity resulting from [K+](o ) elevation. The resulting activity is paced by interictal events occu rring in the CA3 pyramidal neuron population. A role for mGluRs in the interictal activity of the CA3 pyramidal neuron population is also de scribed. After the establishment of epileptiform activity, synaptic in hibition onto CA1 pyramidal neurons is severly attenuated. This result s not from the [K+](o) elevation per se but possibly from an activity- dependent Cl- redistribution across the CA1 pyramidal neurons after su stained IPSC activity.