Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour.
Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour.
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DOI：
10.1038/nature18626
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发表时间：
2016-07-21
期刊：
影响因子：
64.8
通讯作者：
Kipnis J
中科院分区：
文献类型：
--
作者：
Filiano AJ;Xu Y;Tustison NJ;Marsh RL;Baker W;Smirnov I;Overall CC;Gadani SP;Turner SD;Weng Z;Peerzade SN;Chen H;Lee KS;Scott MM;Beenhakker MP;Litvak V;Kipnis J
免疫功能障碍通常与几种神经和精神疾病有关。虽然外周免疫可能影响神经元功能的机制在很大程度上是未知的，但最近的研究结果表明脑膜免疫影响行为，如空间学习和记忆。在这里，我们表明脑膜免疫对社会行为也很重要;缺乏适应性免疫的小鼠表现出社会缺陷和额皮质脑区域的超连通性。来自脑的啮齿类动物转录组与响应于T细胞衍生的细胞因子的细胞转录组之间的关联表明社会行为与干扰素-γ（IFN-γ）驱动的响应之间的强相互作用。一致地，我们证明了抑制性神经元对IFN-γ产生反应并增加投射神经元中的GABA能电流，这表明IFN-γ是脑膜免疫和为社会行为募集的神经回路之间的分子联系。对一系列生物体转录组的荟萃分析显示，啮齿动物、鱼类和苍蝇在社会背景下提高了IFN-γ/JAK-STAT依赖性基因特征，这表明IFN-γ信号通路可以介导社会/聚集行为与有效的抗病原体反应之间的共进化联系。这项研究暗示了适应性免疫功能障碍，特别是IFN-γ，在以社会功能障碍为特征的疾病中，并表明了社会行为和IFN-γ信号转导驱动的抗病原体免疫应答之间的共进化联系。
Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behavior, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behavior; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T cell–derived cytokines suggest a strong interaction between social behavior and interferon-gamma (IFN-γ) driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behavior. Meta-analysis on the transcriptomes of a range of organisms revealed that rodents, fish, and flies elevate IFN-γ/JAK-STAT–dependent gene signatures in a social context, suggesting that the IFN-γ signaling pathway could mediate a co-evolutionary link between social/aggregation behavior and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behavior and an anti-pathogen immune response driven by IFN-γ signaling.