Neitz A, Mergia E, Neubacher U, Koesling D, Mittmann T
Department of Physiology, UMC of the Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany,
Pflugers Arch. 2015 Jun;467(6):1383-94. doi: 10.1007/s00424-014-1571-6. Epub 2014 Jul 11.
GABAergic interneurons are the predominant source of inhibition in the brain that coordinate the level of excitation and synchronization in neuronal circuitries. However, the underlying cellular mechanisms are still not fully understood. Here we report nitric oxide (NO)/NO-GC1 signalling as an important regulatory mechanism of GABAergic and glutamatergic synaptic transmission in the hippocampal CA1 region. Deletion of the NO receptor NO-GC1 induced functional alterations, indicated by a strong reduction of spontaneous and evoked inhibitory postsynaptic currents (IPSCs), which could be compensated by application of the missing second messenger cGMP. Moreover, we found a general impairment in the strength of inhibitory and excitatory synaptic inputs onto CA1 pyramidal neurons deriving from NO-GC1KO mice. Finally, we disclosed one subpopulation of GABAergic interneurons, fast-spiking interneurons, that receive less excitatory synaptic input and consequently respond with less spike output after blockage of the NO/cGMP signalling pathway. On the basis of these and previous findings, we propose NO-GC1 as the major NO receptor which transduces the NO signal into cGMP at presynaptic terminals of different neuronal subtypes in the hippocampal CA1 region. Furthermore, we suggest NO-GC1-mediated cGMP signalling as a mechanism which regulates the strength of synaptic transmission, hence being important in gating information processing between hippocampal CA3 and CA1 region.
γ-氨基丁酸能中间神经元是大脑中抑制作用的主要来源，它们协调神经元回路中的兴奋水平和同步性。然而，其潜在的细胞机制仍未完全了解。在此，我们报告一氧化氮（NO）/ NO-鸟苷酸环化酶1（NO-GC1）信号传导是海马CA1区γ-氨基丁酸能和谷氨酸能突触传递的重要调节机制。NO受体NO-GC1的缺失导致功能改变，表现为自发和诱发的抑制性突触后电流（IPSC）大幅减少，而应用缺失的第二信使环磷酸鸟苷（cGMP）可对此进行补偿。此外，我们发现来自NO-GC1基因敲除小鼠的CA1锥体神经元上的抑制性和兴奋性突触输入强度普遍受损。最后，我们揭示了γ-氨基丁酸能中间神经元的一个亚群，即快发放中间神经元，在NO / cGMP信号通路被阻断后，它们接受的兴奋性突触输入减少，因此产生的动作电位输出也减少。基于这些及先前的研究结果，我们提出NO-GC1是主要的NO受体，它在海马CA1区不同神经元亚型的突触前末端将NO信号转化为cGMP。此外，我们认为NO-GC1介导的cGMP信号传导是一种调节突触传递强度的机制，因此在控制海马CA3区和CA1区之间的信息处理中起重要作用。
