The Journal of Neurophysiology Vol. 85 No. 5 May 2001, pp. 1932-1940
Copyright ©2001 by the American Physiological Society

Lack of Effect of Mossy Fiber-Released Zinc on Granule Cell GABA_A Receptors in the Pilocarpine Model of Epilepsy

Department of Pharmacology and Cancer Biology and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710

Molnár, Péter and J. Victor Nadler. Lack of Effect of Mossy Fiber-Released Zinc on Granule Cell GABA_A Receptors in the Pilocarpine Model of Epilepsy. J. Neurophysiol. 85: 1932-1940, 2001. The recurrent mossy fiber pathway of the dentate gyrus expands dramatically in the epileptic brain and serves as a mechanism for synchronization of granule cell epileptiform activity. It has been suggested that this pathway also promotes epileptiform activity by inhibiting GABA_A receptor function through release of zinc. Hippocampal slices from pilocarpine-treated rats were used to evaluate this hypothesis. The rats had developed status epilepticus after pilocarpine administration, followed by robust recurrent mossy fiber growth. The ability of exogenously applied zinc to depress GABA_A receptor function in dentate granule cells depended on removal of polyvalent anions from the superfusion medium. Under these conditions, 200 µM zinc reduced the amplitude of the current evoked by applying muscimol to the proximal portion of the granule cell dendrite (23%). It also reduced the mean amplitude (31%) and frequency (36%) of miniature inhibitory postsynaptic currents. Nevertheless, repetitive mossy fiber stimulation (10 Hz for 1 s, 100 Hz for 1 s, or 10 Hz for 5 min) at maximal intensity did not affect GABA_A receptor-mediated currents evoked by photorelease of GABA onto the proximal portion of the dendrite, where recurrent mossy fiber synapses were located. These results could not be explained by stimulation-induced depletion of zinc from the recurrent mossy fiber boutons. Negative results were obtained even during exposure to conditions that promoted transmitter release and synchronized granule cell activity (6 mM [K⁺]_o, nominally Mg²⁺-free medium, 33°C). These results suggest that zinc released from the recurrent mossy fiber pathway did not reach a concentration at postsynaptic GABA_A receptors sufficient to inhibit agonist-evoked activation.