Received for publication May 18, 2007.
Revised October 30, 2007.
Accepted for publication October 30, 2007.

Differential Effects of Methylmercury on GABA_A Receptor Currents in Rat Cerebellar Granule and Cerebral Cortical Neurons in Culture

Abstract

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 IPSCs/IPSPs 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 which 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 (DIV 4, 6, 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 HEK-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.

Key words: GABA-A receptor, HEK-293 cell, cerebellar granule cell, chloride current, cortical neuron, methylmercury, neurotoxicity