Activity-Dependent Zinc Release from Hippocampal Mossy Fibers Inhibits Kainate Receptor Function.
Abstract number :
1.010
Submission category :
Year :
2001
Submission ID :
3091
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
D.D. Mott, Ph.D., Pharmacology, Emory University School of Medicine, Atlanta, GA; R. Dingledine, Ph.D., Pharmacology, Emory University School of Medicine, Atlanta, GA
RATIONALE: Kainate receptors have been implicated in the pathogenesis of epilepsy and contribute to seizures in hippocampal area CA3. The epileptogenic effect of these receptors may result from their ability to both reduce GABAergic inhibition and directly excite principal cells. We have previously shown that kainate receptors are regulated by a host of physiological modulators, including but not limited to protons, polyamines and redox agents. Kainate receptors are also inhibited by zinc. Zinc inhibition of kainate receptors is subunit dependent, with GluR6/KA2 receptors being more than 18 fold more zinc sensitive than GluR6 receptors. The hippocampal mossy fiber pathway contains high concentrations of vesicular zinc which is co-released with glutamate at synapses. We have examined whether kainate receptors at mossy fiber synapses onto CA3 pyramidal cells are inhibited by zinc released from mossy fibers.
METHODS: Field EPSPs (fEPSP) were evoked in area CA3 of adult rat hippocampal slices by stimulation in the dentate granule cell layer to activate mossy fibers (200 Hz, 4 pulses every 200 ms for 1 sec). ACSF contained 1.5 mM Ca2+ and 1.5 mM Mg2+. fEPSPs were blocked by DCG-IV (1 [mu]M), demonstrating that they were produced by mossy fiber stimulation. Kainate receptor-mediated fEPSPs were isolated using LY303070 (30 [mu]M), D-APV (100 [mu]M) and bicuculline methiodide (100 [mu]M). These fEPSPs were blocked by 100 [mu]M CNQX, but not 1.5 [mu]M CNQX, indicating that they were kainate receptor-mediated.
RESULTS: Exogenous zinc (30 [mu]M) reversibly inhibited the kainate fEPSP by 44 [plusminus] 12% (P [lt] 0.05, n = 4), indicating that native kainate receptors are sensitive to inhibition by zinc. In contrast, the zinc chelators CaEDTA (2.5 mM) and BTC-5N (100 [mu]M) enhanced the kainate fEPSP by 21 [plusminus] 6 (n = 5) and 60 [plusminus] 21% (n = 3), respectively.
CONCLUSIONS: These results suggest that activity dependent release of zinc regulates kainate neurotransmission at mossy fiber synapses.
Support: the Epilepsy Foundation (DM), NARSAD (DM) and the NIH (RD, DM).