Modest increase in extracellular potassium unmasks effect of recurrent mossy fiber growth.

The recurrent mossy fiber pathway of the dentate gyrus expands dramatically in many persons with temporal lobe epilepsy. The new connections among granule cells provide a novel mechanism of synchronization that could enhance the participation of these cells in seizures. Despite the presence of robust recurrent mossy fiber growth, orthodromic or antidromic activation of granule cells usually does not evoke repetitive discharge. This study tested the ability of modestly elevated [K(+)](o), reduced GABA(A) receptor-mediated inhibition and frequency facilitation to unmask the effect of recurrent excitation. Transverse slices of the caudal hippocampal formation were prepared from pilocarpine-treated rats that either had or had not developed status epilepticus with subsequent recurrent mossy fiber growth. During superfusion with standard medium (3.5 mM K(+)), antidromic stimulation of the mossy fibers evoked epileptiform activity in 14% of slices with recurrent mossy fiber growth. This value increased to approximately 50% when [K(+)](o) was raised to either 4.75 or 6 mM. Addition of bicuculline (3 or 30 microM) to the superfusion medium did not enhance the probability of evoking epileptiform activity but did increase the magnitude of epileptiform discharge if such activity was already present. (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (1 microM), which selectively activates type II metabotropic glutamate receptors present on mossy fiber terminals, strongly depressed epileptiform responses. This result implies a critical role for the recurrent mossy fiber pathway. No enhancement of the epileptiform discharge occurred during repetitive antidromic stimulation at frequencies of 0.2, 1, or 10 Hz. In fact, antidromically evoked epileptiform activity became progressively attenuated during a 10-Hz train. Antidromic stimulation of the mossy fibers never evoked epileptiform activity in slices from control rats under any condition tested. These results indicate that even modest changes in [K(+)](o) dramatically affect granule cell epileptiform activity supported by the recurrent mossy fiber pathway. A small increase in [K(+)](o) reduces the amount of recurrent mossy fiber growth required to synchronize granule cell discharge. Block of GABA(A) receptor-mediated inhibition is less efficacious and frequency facilitation may not be a significant factor.

Duke Scholars

Author J. Victor Nadler Pharmacology & Cancer Biology