Tlr7缺失改变与神经功能相关的基因的表达谱并调节小鼠行为和情境记忆

Tlr7 deletion alters expression profiles of genes related to neural function and regulates mouse behaviors and contextual memory

Tlr7：Toll样受体7，Toll-like receptors 7。Toll样受体（Toll-like receptors, TLR）是参与非特异性免疫（天然免疫）的一类重要蛋白质分子，也是连接非特异性免疫和特异性免疫的桥梁。

The neuronal innate immune system recognizes endogenous danger signals and regulates neuronal development and function. Toll-like receptor 7 (TLR7), one of the TLRs that trigger innate immune responses in neurons, controls neuronal morphology. To further assess the function of TLR7 in the brain, we applied next generation sequencing to investigate the effect of Tlr7 deletion on gene expression in hippocampal and cortical mixed cultures and on mouse behaviors. Since previous in vivo study suggested that TLR7 is more critical for neuronal morphology at earlier developmental stages, we analyzed two time-points (4 and 18 DIV) to represent young and mature neurons, respectively. At 4 DIV, Tlr7 KO neurons exhibited reduced expression of genes involved in neuronal development, synaptic organization and activity and behaviors. Some of these Tlr7-regulated genes are also associated with multiple neurological and neuropsychiatric diseases. TLR7-regulated transcriptomic profiles differed at 18 DIV. Apart from neuronal genes, genes related to glial cell development and differentiation became sensitive to Tlr7 deletion at 18 DIV. Moreover, Tlr7 KO mice exhibited altered behaviors in terms of anxiety, aggression, olfaction and contextual fear memory. Electrophysiological analysis further showed an impairment of long-term potentiation in Tlr7 KO hippocampus. Taken together, these results indicate that TLR7 regulates neural development and brain function, even in the absence of infectious or pathogenic molecules. Our findings strengthen evidence for the role of the neuronal innate immune system in fine-tuning neuronal morphology and activity and implicate it in neuropsychiatric disorders.

神经元先天免疫系统识别内源性危险信号并调节神经元发育和功能。Toll样受体7（TLR7）是触发神经元中先天免疫反应的TLR之一，可控制神经元形态。为了进一步评估TLR7在大脑中的功能，我们应用下一代测序来研究Tlr7缺失对海马和皮质混合培养物中基因表达以及对小鼠行为的影响。由于先前的体内研究表明TLR7对早期发育阶段的神经元形态学更为关键，我们分析了两个时间点(4和18 DIV)，分别代表年轻和成熟的神经元。在4 DIV时，Tlr7 KO神经元表现出参与神经元发育、突触组织、活动和行为的基因表达减少。这些Tlr7调节基因中的一些也与多种神经和神经精神疾病相关。TLR7调节的转录组谱在18 DIV时不同。除神经元基因外，与胶质细胞发育和分化相关的基因在18DIV时对Tlr7缺失变得敏感。此外，Tlr7 KO小鼠在焦虑，攻击性，嗅觉和情境恐惧记忆方面表现出改变的行为。电生理分析进一步显示Tlr7 KO海马的长期增强受损。总之，这些结果表明TLR7调节神经发育和脑功能，即使在没有感染性或致病性分子的情况下也是如此。我们的研究结果加强了神经元先天免疫系统在微调神经元形态和活动中的作用的证据，并将其与神经精神疾病相关联。

2018 Aug 发表于Brain Behav Immun（IF6.17）

key words：Aggression;Anxiety;Contextual fear memory（情境恐惧记忆 ）;Next generation sequencing;Toll-like receptor;Transcriptomic profiling;