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Methylmercury differentially affects GABA_A receptor-mediated spontaneous IPSCs in Purkinje and granule cells of rat cerebellar slices

Yukun Yuan and William D. Atchison

Using whole-cell recording techniques we compared effects of the environmental cerebellar neurotoxicant methylmercury (MeHg) on spontaneous IPSCs (sIPSCs) of both Purkinje and granule cells in cerebellar slices of the rat. In Purkinje cells, bath application of 10, 20 or 100 µM MeHg initially increased then suppressed the frequency of sIPSCs to zero. In granule cells, the initial increase in frequency was not observed in ~50 % of cells examined, but suppression of sIPSCs by MeHg occurred in every cell tested. For both cells, time to onset of effects of MeHg was inversely related to the concentration; moreover, the pattern of changes in mIPSCs induced by MeHg in the presence of tetrodotoxin was similar to that in sIPSCs. For each concentration of MeHg, it took 2-3 times longer to block sIPSCs in Purkinje cells than it did in granule cells. MeHg also initially increased then decreased amplitudes of sIPSCs to block in both cells; again the response was more variable in granule cells. In most Purkinje and some granule cells, MeHg induced a giant, slow inward current during the late stages of exposure. Appearance of this current appeared to be MeHg concentration dependent, and the direction of current flow was reversed by changing the holding potentials. Reduction of the [Cl^-] in the internal solution caused inwardly directed, but not outwardly directed giant currents to disappear, suggesting that this current is a Cl^--mediated response. However, bicuculline and picrotoxin failed to block it. MeHg apparently acts at both presynaptic and postsynaptic sites to alter GABA_A receptor-mediated inhibitory synaptic transmission. GABA_A receptors in granule cells appear to be more sensitive to block by MeHg than are those in Purkinje cells, although the general patterns of effects on the two cells are similar.

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				C. J. Herden, N. E. Pardo, R. K. Hajela, Y. Yuan, and W. D. Atchison Differential Effects of Methylmercury on {gamma}-Aminobutyric Acid Type A Receptor Currents in Rat Cerebellar Granule and Cerebral Cortical Neurons in Culture J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 517 - 528. [Abstract] [Full Text] [PDF]

				Y. Yuan and W. D. Atchison Methylmercury-Induced Increase of Intracellular Ca2+ Increases Spontaneous Synaptic Current Frequency in Rat Cerebellar Slices Mol. Pharmacol., April 1, 2007; 71(4): 1109 - 1121. [Abstract] [Full Text] [PDF]

				Y. Yuan and W. D. Atchison Methylmercury Induces a Spontaneous, Transient Slow Inward Chloride Current in Purkinje Cells of Rat Cerebellar Slices J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 751 - 764. [Abstract] [Full Text] [PDF]