The Journal of Neurophysiology Vol. 79 No. 6 June 1998, pp. 3019-3029
Copyright ©1998 The American Physiological Society

Ictal Epileptiform Activity in the CA3 Region of Hippocampal Slices Produced by Pilocarpine

Paul A. Rutecki and Yili Yang

Departments of Neurology, Neurosurgery, and Neuroscience, Training Program, University of Wisconsin Medical School Madison, William S. Middleton VA Hospital, Madison, Wisconsin 53705

Rutecki, Paul A. and Yili Yang. Ictal epileptiform activity in the CA3 region of hippocampal slices produced by pilocarpine. J. Neurophysiol. 79: 3019-3029, 1998. Pilocarpine, a muscarinic agonist, produces status epilepticus that is associated with the later development of chronic recurrent seizures. When applied to rat hippocampal slices, pilocarpine (10 µM) produced brief (<200 ms) epileptiform discharges that resembled interictal activity that occurs between seizures, as well as more prolonged synchronous neuronal activation that lasted seconds (3-20 s), and was comparable to ictal or seizures-like discharges. We assessed the factors that favored ictal patterns of activity and determined the biophysical properties of the ictal discharge. The probability of observing ictal discharges was increased when extracellular potassium ([K⁺]_o) was increased from 5 to 7.5 mM. Raising [K⁺]_o to 10 mM resulted in loss of ictal patterns and, in 20 of 34 slices, desynchronization of epileptiform activity. Making the artificial cerebrospinal fluid (ACSF) hyposmotic favored ictal discharges at 5 mM [K⁺]_o, but shifted 7.5 mM [K⁺]_o ACSF patterns to interictal discharges or desynchronized activity. Conversely, increasing osmolality suppressed ictal patterns. The pilocarpine-induced ictal discharges were blocked by atropine (1 µM, n = 5), a muscarinic antagonist, and pirenzepine (1 µM, n = 6), a selective M₁ receptor antagonist. Kainate/-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor blockade stopped all epileptiform activity (n = 8). The N-methyl-D-aspartate antagonist D,L-2-amino-5-phosphonovaleric acid (100 µM, n = 34) did not change the pattern of epileptiform activity but significantly increased the rate of interictal discharges and prolonged the duration of ictal discharges. The ictal discharge was characterized intracellularly by a depolarization that was associated with action potential generation and persisted as a membrane oscillation of 4-10 Hz. The ictal oscillations reversed in polarity at 22.7 ± 2.2 mV (n = 11) with current-clamp recordings and 20.9 ± 3.1 mV (n = 7) with voltage-clamp recordings. The reversal potential of the ictal discharge in the presence of the -aminobutyric acid-A blocker bicuculline (10 µM, n = 6) was 2.2 ± 2.6 mV and was significantly different from that measured without bicuculline. Bicuculline added to 7.5 mM [K+]_o and 10 µM pilocarpine did not cause epileptiform activity to change pattern but significantly increased the rate of interictal discharges and prolonged the ictal discharge duration. Both synaptic and nonsynaptic mechanisms are important for the generation of ictal patterns of epileptiform activity. Although the synchronous epileptiform activity produced by pilocarpine required fast glutamate-mediated synaptic transmission, the transition from an interictal to ictal pattern of activity depended on [K⁺]_o and could be influenced by extracellular space.

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