NeuroCure Cluster of Excellence, Institute of Integrative Neuroanatomy, Charité, D-10117 Berlin, Germany.
J Neurosci. 2013 May 1;33(18):7961-74. doi: 10.1523/JNEUROSCI.1186-12.2013.
Inhibitory parvalbumin-containing interneurons (PVIs) control neuronal discharge and support the generation of theta- and gamma-frequency oscillations in cortical networks. Fast GABAergic input onto PVIs is crucial for their synchronization and oscillatory entrainment, but the role of metabotropic GABA(B) receptors (GABA(B)Rs) in mediating slow presynaptic and postsynaptic inhibition remains unknown. In this study, we have combined high-resolution immunoelectron microscopy, whole-cell patch-clamp recording, and computational modeling to investigate the subcellular distribution and effects of GABA(B)Rs and their postsynaptic effector Kir3 channels in rat hippocampal PVIs. Pre-embedding immunogold labeling revealed that the receptors and channels localize at high levels to the extrasynaptic membrane of parvalbumin-immunoreactive dendrites. Immunoreactivity for GABA(B)Rs was also present at lower levels on PVI axon terminals. Whole-cell recordings further showed that synaptically released GABA in response to extracellular stimulation evokes large GABA(B)R-mediated slow IPSCs in perisomatic-targeting (PT) PVIs, but only small or no currents in dendrite-targeting (DT) PVIs. In contrast, paired recordings demonstrated that GABA(B)R activation results in presynaptic inhibition at the output synapses of both PT and DT PVIs, but more strongly in the latter. Finally, computational analysis indicated that GABA(B) IPSCs can phasically modulate the discharge of PT interneurons at theta frequencies. In summary, our results show that GABA(B)Rs differentially mediate slow presynaptic and postsynaptic inhibition in PVIs and can contribute to the dynamic modulation of their activity during oscillations. Furthermore, these data provide evidence for a compartment-specific molecular divergence of hippocampal PVI subtypes, suggesting that activation of GABA(B)Rs may shift the balance between perisomatic and dendritic inhibition.
抑制性含有 Parvalbumin 的中间神经元（PVIs）控制神经元放电，并支持皮质网络中θ和γ频率振荡的产生。快速 GABA 能传入到 PVIs 对它们的同步和振荡同步至关重要，但代谢型 GABA（B）受体（GABA（B）Rs）在介导慢突触前和突触后抑制中的作用仍然未知。在这项研究中，我们结合了高分辨率免疫电子显微镜、全细胞膜片钳记录和计算建模，以研究 GABA（B）Rs 及其突触后效应器 Kir3 通道在大鼠海马 PVIs 中的亚细胞分布和作用。预包埋免疫金标记显示，受体和通道高度定位于 Parvalbumin 免疫反应性树突的 extrasynaptic 膜上。GABA（B）Rs 的免疫反应性也以较低水平存在于 PVI 轴突末梢。全细胞膜片钳记录进一步表明，细胞外刺激引发的突触释放 GABA 会在躯体靶向（PT）PVIs 中引起大的 GABA（B）R 介导的慢 IPSC，但在树突靶向（DT）PVIs 中只会引起小或无电流。相比之下，配对记录表明，GABA（B）R 激活导致 PT 和 DT PVIs 的输出突触的 presynaptic 抑制，但在后一种情况下更为强烈。最后，计算分析表明，GABA（B）IPSCs 可以在 theta 频率下调节 PT 中间神经元的放电。总之，我们的结果表明，GABA（B）Rs 以不同的方式介导 PVIs 中的慢突触前和突触后抑制，并有助于它们在振荡过程中活性的动态调节。此外，这些数据为海马体 PVI 亚型的特定隔室分子差异提供了证据，表明 GABA（B）R 的激活可能会改变躯体和树突抑制之间的平衡。
