Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome.
Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome.
复制标题
有证据表明，在唐氏综合症 Ts65Dn 小鼠模型中，增加 Kcnj6 基因剂量对于行为和齿状回突触可塑性缺陷是必要的。
DOI：
10.1016/j.nbd.2017.03.009
复制
发表时间：
2017-07
影响因子：
6.1
通讯作者：
Mobley WC
中科院分区：
文献类型：
--
作者：
Kleschevnikov AM;Yu J;Kim J;Lysenko LV;Zeng Z;Yu YE;Mobley WC
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.
