Diversity of GABA(A) receptor synaptic currents on individual pyramidal cortical neurons

Abstract

Miniature GABA(A) receptor-mediated inhibitory postsynaptic currents (mIPSCs) in cortical pyramidal neurons have previously been categorized into two types: small amplitude mIPSCs with a mono-exponential deactivation (mono-mIPSCs) and relatively larger mIPSCs with bi-exponential deactivation (bi-mIPSCs). The aim of this study was to determine if the GABA(A) channels that underlie these mIPSCSs are molecularly distinct. We found, using non-stationary noise analysis, that the difference in their amplitude could be not accounted for by their single channel conductance (both were 40 pS). Next, using alpha subunit selective GABA(A) receptor modulators, we examined the identity of the alpha subunits that may be expressed in the synapses that give rise to these mIPSCs. Zolpidem (100 and 500 nM, alpha1 selective) affected the deactivation of a subset of the mono-mIPSCs, indicating that alpha1 subunits are not highly expressed in these synapses. However, zolpidem (100 nM) prolonged the deactivation of all bi-mIPSCs, indicating a high abundance of alpha1 subunits in these synapses. SB-205384 (alpha3 selective) had no effect on the mono-mIPSCs but the bi-mIPSCs were prolonged. Furosemide (alpha4 selective) reduced the amplitude of only the mono-mIPSCs. L655,708 (alpha5 selective) reduced the amplitude of both populations and shortened the duration of the mono-mIPSCs. Finally, we found that the neuroactive steroid pregesterone sulphate reduced the amplitude of both mIPSC types. These results provide pharmacological evidence that synapses on cortical pyramidal neurons are molecularly distinct. The purpose of these different types of synapses may be to provide different inhibitory timing patterns on these cells.