BACKGROUND Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-γ modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-β (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-γ. METHODS We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-γ receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (Ih), and inhibitory neurotransmission under the influence of acutely applied IFN-γ. RESULTS We show that IFN-γ receptors are present in the membrane of rat's neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-γ diminished Ih, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-γ did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-γ. Indeed, IFN-γ increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-γ, whereas their frequency remained unchanged. CONCLUSIONS The expression of IFN-γ receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-γ highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-γ in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders.

中文翻译：

---

干扰素-γ急性增强对新皮层5锥体神经元的抑制作用。

背景技术干扰素-γ（IFN-γ，II型IFN）在各种条件下存在于中枢神经系统（CNS）中。越来越多的证据表明，除了其免疫学作用外，IFN-γ还调节着几个大脑区域的神经元形态，功能和发育。以前，我们已经证明，升高IFN-β（一种I型IFN）的水平会导致新皮质5层锥体神经元的神经元兴奋性增加。由于两种细胞因子共有非常规的信号通路，我们假设急性应用的IFN-γ具有类似的新皮层作用。方法我们使用半定量RT-PCR，免疫印迹和免疫组化分析了IFN-γ受体的神经元表达，并在第5层锥体神经元中进行了全细胞膜片钳记录，以研究亚阈上和阈上兴奋性，极化环门控电流（Ih）的超极化特性和在急性应用IFN-γ影响下的抑制性神经传递。结果我们显示，在大鼠新皮层5锥体神经元的膜中存在IFN-γ受体。正如从此以及推定的I型和II型IFN替代信号通路的重叠所期望的，IFN-γ降低了Ih，反映了I型IFN的作用，表明蛋白激酶C（PKC）也同样被激活。相反，IFN-γ既没有改变阈下阈值也没有改变阈上阈值的神经元兴奋性，这表明IFN-γ增加了抑制性传递。确实，IFN-γ增加了新皮层5锥体神经元上的电诱发的突触后抑制电流（IPSC）。此外，IFN-γ可提高自发IPSC和微型IPSC的振幅，而它们的频率保持不变。结论IFN-γ受体在第5层新皮层锥体神经元上的表达以及通过直接应用IFN-γ在新皮层中的抑制作用的急性增强突显了CNS与免疫系统之间的额外相互作用。我们的结果加强了我们对IFN-γ在新皮层神经传递中的作用的理解，并强调了其在免疫学特性之外的影响，特别是在神经精神疾病的发病机理中。