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TOXICOLOGY

Differential Effects of Methylmercury on -Aminobutyric Acid Type A Receptor Currents in Rat Cerebellar Granule and Cerebral Cortical Neurons in Culture

Neuroscience Program and Department of Pharmacology/Toxicology, Michigan State University, East Lansing, Michigan

Cerebellar granule cells are particularly sensitive to inhibition by methylmercury (MeHg) on GABA_A receptor function. This is manifested as a more rapid block of inhibitory postsynaptic currents/inhibitory postsynaptic potentials than for Purkinje cells. The underlying mechanism(s) for differential sensitivity of GABAergic transmission to MeHg in cerebellar neurons is unknown. Differential expression of ₆ subunit-containing GABA_A receptors in cerebellar granule and Purkinje neurons could partially explain this. GABA-evoked currents (I_GABA) were recorded in response to MeHg in ₆ subunit-containing cerebellar granule cells and ₆ subunit-deficient cerebral cortical cells in culture. Cortical cells were substituted for Purkinje cells, which do not express ₆ subunits. They express the same ₁-containing GABA_A receptor as Purkinje cells but lack characteristics that enhance Purkinje cell resistance to MeHg. I_GABA were obtained using whole-cell recording and symmetrical [Cl^–]. MeHg reduced I_GABA to complete block in both cell types in a time- and concentration-dependent manner. This effect was faster in granule cells than cortical cells. Effects of MeHg on I_GABA were recorded in granule cells at various developmental stages (days in vitro 4, 6, and 8) to alter the expression level of ₆ subunit-containing GABA_A receptors. Effects of MeHg on I_GABA were similar in cells at all days. In human embryonic kidney 293 cells expressing either ₆ or ₁ subunit-containing GABA_A receptors, time to block of I_GABA by MeHg was comparable. Thus, the presence of the ₆ subunit alone may not underlie the differential effects of MeHg on I_GABA observed in cerebellar granule and cortical neurons; other factors are likely to be involved as well.

Address correspondence to: Dr. William D. Atchison, Department of Pharmacology and Toxicology, Michigan State University, B-331 Life Science Building, East Lansing, MI 48824-1317. E-mail: atchiso1{at}msu.edu