Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome.
Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome.
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DOI：
10.1016/j.nbd.2011.10.009
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发表时间：
2012-02
影响因子：
6.1
通讯作者：
Mobley, William C.
中科院分区：
文献类型：
--
作者：
Kleschevnikov, Alexander M.;Belichenko, Pavel V.;Gall, Jessica;George, Lizzy;Nosheny, Rachel;Maloney, Michael T.;Salehi, Ahmad;Mobley, William C.
关键词：
唐氏综合症（DS）的认知障碍涉及海马体。在 DS 的 Ts65Dn 小鼠模型中，海马依赖性学习和突触可塑性的缺陷与抑制作用的增强有关。然而，抑制效率变化的机制基础在很大程度上仍未被探索，并且 GABA 能突触神经传递的效率尚未在直接电生理学实验中进行研究。为了研究 DS 神经生物学的这一重要特征，我们检查了成年 Ts65Dn 小鼠齿状回 (DG) 中 GABA 能系统的突触和分子特性。与对照 (2N) DG 颗粒细胞相比，Ts65Dn 中 GABAA 和 GABAB 受体介导的诱发抑制性突触后电流 (IPSC) 成分均显着增加。这些变化并未伴随海马 GABAA（α1、α2、α3、α5 和 γ2）或 GABAB（Gbr1a 和 Gbr1b）受体亚基水平的变化。 GAD65（GABA 能末端标记）的免疫反应性也没有变化。相比之下，GABA能突触的功能参数发生了显着变化。配对刺激显示 GABAA 和 GABAB 受体介导的 IPSC 成分 (IPSC2/IPSC1) 的配对脉冲比率降低，表明 GABA 突触前释放增加。与基因剂量增加一致，钾通道 Kir3.2 亚基（突触后 GABAB 受体的效应器）的水平也增加。这种变化与应用 GABAB 受体激动剂巴氯芬后突触后 GABAB/Kir3.2 信号传导增强有关。因此，Ts65Dn DG 中 GABAA 和 GABAB 受体介导的突触效率均增加，因此可能导致 DS 中突触可塑性不足和学习不良。
Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (α1, α2, α3, α5 and γ2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS.
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影响因子：
2.5
作者：
Belichenko, PV;Masliah, E;Mobley, WC
通讯作者：
Mobley, WC
DOI：
10.1073/pnas.93.23.13333
发表时间：
1996-11-12
影响因子：
11.1
作者：
Holtzman, DM;Santucci, D;Mobley, WC
通讯作者：
Mobley, WC
DOI：
10.1073/pnas.0904397106
发表时间：
2009-10-06
影响因子：
11.1
作者：
Chang, Karen T.;Min, Kyung-Tai
通讯作者：
Min, Kyung-Tai
影响因子：
2.5
作者：
Belichenko, Pavel V.;Klescrevnikov, Alexander M.;Mobley, William C.
通讯作者：
Mobley, William C.
影响因子：
5.3
作者：
Belichenko, Nadia P.;Belichenko, Pavel V.;Mobley, William C.
通讯作者：
Mobley, William C.