Yamada Junko, Furukawa Tomonori, Ueno Shinya, Yamamoto Sumii, Fukuda Atsuo
Department of Biological Information Processing, Graduate School of Electronic Science and Technology, Shizuoka University, Hamamatsu, Shizuoka 432-8011, Japan.
Cereb Cortex. 2007 Aug;17(8):1782-7. doi: 10.1093/cercor/bhl087. Epub 2006 Sep 22.
Fast inhibitory synaptic transmission is primarily mediated by synaptically released gamma-aminobutyric acid (GABA) acting on postsynaptic GABA(A) receptors. GABA acting on GABA(A) receptors produces not only phasic but also tonic inhibitions by persistent activation of extrasynaptic receptors. However, the mechanistic characteristics of tonic inhibition in the neocortex are not well-understood. To address this, we studied pharmacologically isolated GABA(A) receptor-mediated currents in neocortical pyramidal neurons in rat brain slices. Bath application of bicuculline blocked miniature inhibitory postsynaptic currents (mIPSCs) and produced an outward shift in baseline holding current (I(hold)). Low concentrations of SR95531, a competitive GABA(A) receptor antagonist, abolished mIPSCs but had no significant effect on I(hold). The benzodiazepine midazolam produced an inward shift in I(hold) by augmenting tonic GABA(A) receptor-mediated currents, which were significantly greater in layer V neurons than in layer II/III. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a relatively higher expressions of alpha1 and alpha5 subunit mRNA in layer V neurons. L-655708, an alpha5 subunit-specific inverse agonist, reduced tonic currents in layer V but not in layer II/III neurons, whereas zolpidem, an alpha1-subunit agonist, exerted equivalent effects in both layers. These data suggest that the alpha1 GABA(A) receptor subunit is generally involved in tonic inhibition in pyramidal neurons of the neocortex, whereas the alpha5 subunit is specifically involved in layer V neurons.
快速抑制性突触传递主要由突触释放的γ-氨基丁酸（GABA）作用于突触后GABA（A）受体介导。作用于GABA（A）受体的GABA不仅通过突触外受体的持续激活产生相位性抑制，还产生紧张性抑制。然而，新皮层中紧张性抑制的机制特征尚未得到很好的理解。为了解决这个问题，我们研究了大鼠脑片中新皮层锥体神经元中药物分离的GABA（A）受体介导的电流。浴用荷包牡丹碱阻断微小抑制性突触后电流（mIPSCs），并使基线钳制电流（I(hold)）向外偏移。低浓度的SR95531，一种竞争性GABA（A）受体拮抗剂，消除了mIPSCs，但对I(hold)没有显著影响。苯二氮䓬类药物咪达唑仑通过增强紧张性GABA（A）受体介导的电流使I(hold)向内偏移，V层神经元中的这种电流明显大于II/III层。单细胞逆转录酶-聚合酶链反应（RT-PCR）显示V层神经元中α1和α5亚基mRNA的表达相对较高。α5亚基特异性反向激动剂L-655708降低了V层但未降低II/III层神经元的紧张性电流，而α1亚基激动剂唑吡坦在两层中产生了等效作用。这些数据表明，α1 GABA（A）受体亚基通常参与新皮层锥体神经元的紧张性抑制，而α5亚基则特异性参与V层神经元。
