Kleschevnikov Alexander M, Yu Jessica, Kim Jeesun, Lysenko Larisa V, Zeng Zheng, Yu Y Eugene, Mobley William C
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Neurobiol Dis. 2017 Jul;103:1-10. doi: 10.1016/j.nbd.2017.03.009. Epub 2017 Mar 22.
Down syndrome (DS), trisomy 21, is caused by increased dose of genes present on human chromosome 21 (HSA21). The gene-dose hypothesis argues that a change in the dose of individual genes or regulatory sequences on HSA21 is necessary for creating DS-related phenotypes, including cognitive impairment. We focused on a possible role for Kcnj6, the gene encoding Kir3.2 (Girk2) subunits of a G-protein-coupled inwardly-rectifying potassium channel. This gene resides on a segment of mouse Chromosome 16 that is present in one extra copy in the genome of the Ts65Dn mouse, a well-studied genetic model of DS. Kir3.2 subunit-containing potassium channels serve as effectors for a number of postsynaptic metabotropic receptors including GABAB receptors. Several studies raise the possibility that increased Kcnj6 dose contributes to synaptic and cognitive abnormalities in DS. To assess directly a role for Kcnj6 gene dose in cognitive deficits in DS, we produced Ts65Dn mice that harbor only 2 copies of Kcnj6 (Ts65Dn:Kcnj6++- mice). The reduction in Kcnj6 gene dose restored to normal the hippocampal level of Kir3.2. Long-term memory, examined in the novel object recognition test with the retention period of 24h, was improved to the level observed in the normosomic littermate control mice (2N:Kcnj6++). Significantly, both short-term and long-term potentiation (STP and LTP) was improved to control levels in the dentate gyrus (DG) of the Ts65Dn:Kcnj6++- mouse. In view of the ability of fluoxetine to suppress Kir3.2 channels, we asked if fluoxetine-treated DG slices of Ts65Dn:Kcnj6+++ mice would rescue synaptic plasticity. Fluoxetine increased STP and LTP to control levels. These results are evidence that increased Kcnj6 gene dose is necessary for synaptic and cognitive dysfunction in the Ts65Dn mouse model of DS. Strategies aimed at pharmacologically reducing channel function should be explored for enhancing cognition in DS.
唐氏综合征（DS），即21三体综合征，是由人类21号染色体（HSA21）上基因剂量增加所致。基因剂量假说认为，HSA21上单个基因或调控序列剂量的改变对于产生包括认知障碍在内的唐氏综合征相关表型是必要的。我们聚焦于Kcnj6的可能作用，该基因编码G蛋白偶联内向整流钾通道的Kir3.2（Girk2）亚基。该基因位于小鼠16号染色体的一个片段上，在Ts65Dn小鼠的基因组中存在一个额外拷贝，Ts65Dn小鼠是一种经过充分研究的唐氏综合征遗传模型。含Kir3.2亚基的钾通道作为包括GABAB受体在内的多种突触后代谢型受体的效应器。多项研究提出，Kcnj6剂量增加可能导致唐氏综合征的突触和认知异常。为了直接评估Kcnj6基因剂量在唐氏综合征认知缺陷中的作用，我们培育了仅携带2个Kcnj6拷贝的Ts65Dn小鼠（Ts65Dn:Kcnj6++-小鼠）。Kcnj6基因剂量的降低使海马中Kir3.2的水平恢复正常。在24小时保留期的新物体识别试验中检测的长期记忆，改善到了正常染色体同窝对照小鼠（2N:Kcnj6++）所观察到的水平。重要的是，Ts65Dn:Kcnj6++-小鼠齿状回（DG）中的短期和长期增强（STP和LTP）均改善到了对照水平。鉴于氟西汀能够抑制Kir3.2通道，我们询问氟西汀处理的Ts65Dn:Kcnj6+++小鼠的DG切片是否能挽救突触可塑性。氟西汀将STP和LTP提高到了对照水平。这些结果证明，在Ts65Dn唐氏综合征小鼠模型中，Kcnj6基因剂量增加对于突触和认知功能障碍是必要的。应探索旨在通过药理学降低通道功能的策略以增强唐氏综合征患者的认知能力。
