AUTHOR=Guo Yu-Peng , Zhi Yu-Ru , Liu Ting-Ting , Wang Yun , Zhang Ying 

TITLE=Global Gene Knockout of Kcnip3 Enhances Pain Sensitivity and Exacerbates Negative Emotions in Rats

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=12

YEAR=2019

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00005

DOI=10.3389/fnmol.2019.00005

ISSN=1662-5099

ABSTRACT=<p>The Ca<sup>2+</sup>-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 <italic>Kcnip3</italic><sup>-/-</sup> mice have indicated that KChIP3 facilitates pain hypersensitivity by repressing <italic>Pdyn</italic> expression in the spinal cord. Conversely, studies from transgenic daDREAM (dominant active DREAM) mice indicated that KChIP3 contributes to analgesia by repressing <italic>Bdnf</italic> 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 <italic>Kcnip3</italic><sup>-/-</sup> 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, <italic>Kcnip3</italic><sup>-/-</sup> 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 <italic>Kcnip3</italic><sup>-/-</sup> rats. Among the 68 upregulated genes, 19 genes (including <italic>Nr4a2, Ret, Cplx3, Rgs9</italic>, and <italic>Itgad</italic>) are associated with neural development or synaptic transmission, particularly dopamine neurotransmission. Among the 79 downregulated genes, 16 genes (including <italic>Col3a1, Itm2a, Pcdhb3, Pcdhb22, Pcdhb20, Ddc</italic>, and <italic>Sncaip</italic>) are associated with neural development or dopaminergic transmission. Transcriptional upregulation of <italic>Nr4a2, Ret, Cplx3</italic> and <italic>Rgs9</italic>, and downregulation of <italic>Col3a1, Itm2a, Pcdhb3</italic> and <italic>Ddc</italic>, were validated by qPCR analysis. In summary, our studies showed that <italic>Kcnip3</italic><sup>-/-</sup> rats displayed higher pain sensitivity and stronger negative emotions, suggesting an involvement of KChIP3 in negative emotions and possible role in central nociceptive processing.</p>