Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats
Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats
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Kcnip3 的整体基因敲除增强了大鼠的疼痛敏感性并加剧了负面情绪
DOI：
10.3389/fnmol.2019.00005
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发表时间：
2019-01-25
影响因子：
4.8
通讯作者：
Zhang, Ying
中科院分区：
文献类型：
--
作者：
Guo, Yu-Peng;Zhi, Yu-Ru;Zhang, Ying
钙离子结合蛋白Kv通道相互作用蛋白3（KChIP 3）或下游调节元件拮抗剂调节剂（DREAM）是神经元钙传感器（NCS）家族的一员，具有显著的多功能特性。它作为细胞核中的转录抑制因子和离子通道或受体的调节剂，如细胞膜上的Kv 4、NMDA受体和TRPV 1通道。先前对Kcnip 3-/-小鼠的研究表明，KChIP 3通过抑制脊髓中的Pdyn表达而促进疼痛超敏反应。相反，转基因daDREAM（显性活性DREAM）小鼠的研究表明，KChIP 3通过抑制BDNF表达和减弱中枢致敏作用的发展而有助于镇痛。为了进一步确定KChIP 3在疼痛传递中的作用及其可能参与情绪处理，我们评估了KCNIP 3-/-大鼠的疼痛敏感性和负性情绪行为。与野生型大鼠相比，敲除大鼠在急性伤害性疼痛模型和晚期（即，完全弗氏佐剂注射后2、4和6天）的慢性炎性疼痛模型。重要的是，Kcnip 3-/-大鼠表现出更强的厌恶疼痛相关的隔间，更高的焦虑水平和加重抑郁样行为。此外，在野生型和Kcnip 3-/-大鼠之间比较前脑皮质的RNA-Seq转录谱。在68个上调的基因中，19个基因（包括Nr 4a 2、Ret、Cplx 3、Rgs 9和Itgad）与神经发育或突触传递相关，特别是多巴胺神经传递。在79个下调基因中，有16个基因（包括Col 3a 1、Itm 2a、Pcdhb 3、Pcdhb 22、Pcdhb 20、Ddc和Sncaip）与神经发育或多巴胺能传递相关。通过qPCR分析验证Nr 4a 2、Ret、Cplx 3和Rgs 9的转录上调以及Col 3a 1、Itm 2a、Pcdhb 3和Ddc的下调。综上所述，我们的研究表明，Kcnip 3-/-大鼠表现出更高的疼痛敏感性和更强的负性情绪，这表明KChIP 3参与了负性情绪和中枢伤害性加工的可能作用。
The Ca2+-binding protein Kv channel interacting protein 3 (KChIP3) or downstream regulatory element antagonist modulator (DREAM), a member of the neuronal calcium sensor (NCS) family, shows remarkable multifunctional properties. It acts as a transcriptional repressor in the nucleus and a modulator of ion channels or receptors, such as Kv4, NMDA receptors and TRPV1 channels on the cytomembrane. Previous studies of Kcnip3-/- mice have indicated that KChIP3 facilitates pain hypersensitivity by repressing Pdyn expression in the spinal cord. Conversely, studies from transgenic daDREAM (dominant active DREAM) mice indicated that KChIP3 contributes to analgesia by repressing Bdnf expression and attenuating the development of central sensitization. To further determine the role of KChIP3 in pain transmission and its possible involvement in emotional processing, we assessed the pain sensitivity and negative emotional behaviors of Kcnip3-/- rats. The knockout rats showed higher pain sensitivity compared to the wild-type rats both in the acute nociceptive pain model and in the late phase (i.e., 2, 4 and 6 days post complete Freund’s adjuvant injection) of the chronic inflammatory pain model. Importantly, Kcnip3-/- rats displayed stronger aversion to the pain-associated compartment, higher anxiety level and aggravated depression-like behavior. Furthermore, RNA-Seq transcriptional profiling of the forebrain cortex were compared between wild-type and Kcnip3-/- rats. Among the 68 upregulated genes, 19 genes (including Nr4a2, Ret, Cplx3, Rgs9, and Itgad) are associated with neural development or synaptic transmission, particularly dopamine neurotransmission. Among the 79 downregulated genes, 16 genes (including Col3a1, Itm2a, Pcdhb3, Pcdhb22, Pcdhb20, Ddc, and Sncaip) are associated with neural development or dopaminergic transmission. Transcriptional upregulation of Nr4a2, Ret, Cplx3 and Rgs9, and downregulation of Col3a1, Itm2a, Pcdhb3 and Ddc, were validated by qPCR analysis. In summary, our studies showed that Kcnip3-/- rats displayed higher pain sensitivity and stronger negative emotions, suggesting an involvement of KChIP3 in negative emotions and possible role in central nociceptive processing.