Synaptically-Released Zinc Inhibits NMDA Receptor Activation and NMDA Receptor-Mediated Bursting Evoked by Recurrent Mossy Fiber Stimulation.
Abstract number :
A.03
Submission category :
Year :
2001
Submission ID :
205
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
P. Molnar, Ph.D., Pharmacology and Neurobiology, Duke Univ Med Ctr, Durham, NC; J.V. Nadler, Ph.D., Pharmacology and Neurobiology, Duke Univ Med Ctr, Durham, NC
RATIONALE: The recurrent mossy fiber pathway of epileptic brain serves as a mechanism for synchronizing dentate granule cell epileptiform activity and may therefore facilitate seizure propagation. Zinc is coreleased with glutamate from mossy fiber boutons and might either promote or attenuate epileptiform activity. A previous study provided no support for the hypothesis that released zinc promotes epileptiform activity by inhibiting activation of nearby GABA[sub]A[/sub] receptors on the granule cell dendrite. The present study considered the possibility that released zinc could attenuate epileptiform activity through NMDA receptor antagonism.
METHODS: Transverse hippocampal slices were prepared from pilocarpine-treated rats that had developed status epilepticus, with subsequent recurrent mossy fiber growth. Effects of zinc were assessed from the ability of the zinc chelator calcium disodium edetate (CaEDTA; 1 mM) to alter the response of granule cells to mossy fiber stimulation.
RESULTS: Chelation of zinc enhanced the NMDA receptor-mediated component of the recurrent mossy fiber EPSC, but did not affect the AMPA/kainate receptor-mediated component. Its effect was detectable only at negative membrane potentials, suggesting that zinc acted in large part by blocking the NMDA channel. Chelation of zinc did not affect the NMDA receptor-mediated component of the perforant path EPSC. Mossy fiber stimulation in the presence of nominally Mg2+-free medium, 6 mM [K+][sub]o[/sub] and antagonists of AMPA/kainate and GABA[sub]A[/sub] receptors evoked granule cell bursts that were predominantly mediated by NMDA receptor activation. Chelation of zinc accelerated the appearance of evoked bursts after the change of medium. However, chelation of zinc did not alter the magnitude of the evoked bursts once they had fully developed.
CONCLUSIONS: Corelease of zinc at mossy fiber-granule cell synapses reduces the ability of glutamate to activate postsynaptic NMDA receptors. Through this action, zinc can attenuate granule cell epileptiform activity.
Support: NIH grant NS 38108