KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia.
KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia.
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DOI：
10.1038/mp.2015.219
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发表时间：
2016-11
影响因子：
11
通讯作者：
Weinberger DR
中科院分区：
文献类型：
--
作者：
Carr GV;Chen J;Yang F;Ren M;Yuan P;Tian Q;Bebensee A;Zhang GY;Du J;Glineburg P;Xun R;Akhile O;Akuma D;Pickel J;Barrow JC;Papaleo F;Weinberger DR
KCNH 2 -3.1编码人类ether-a-go-go-related（hERG）钾通道的灵长类动物特异性和脑选择性亚型，人类KCNH 2 -3.1的过度表达与认知受损、神经处理效率低下和精神分裂症有关。在这里，我们描述了一种新的小鼠模型，纳入KCNH 2 -3.1分子表型。KCNH 2 -3.1转基因小鼠存活并显示正常的感觉运动行为。然而，他们显示海马和前额皮质的神经元结构和微电路功能发生了变化，这些区域在精神分裂症中受到影响。具体而言，在海马CA 1区的切片制备中，KCNH 2 -3.1转基因小鼠的成熟树突较少，θ爆发刺激长时程增强（TBS-LTP）受损。在前额叶皮层也观察到KCNH 2 -3.1亚型快速失活动力学特征的异常神经元放电模式。转基因小鼠表现出显着的赤字，在一个依赖于大脑皮层的目标定位任务和前额叶皮层依赖的T-迷宫工作记忆任务。有趣的是，在幼年转基因小鼠中不存在这种依赖于基因组的改变，这表明了表型的发育轨迹。抑制KCNH 2 -3.1在成年小鼠中的表达拯救了行为和生理表型。这些数据提供了深入了解KCNH 2 -3.1与人类认知和神经元生理学变化相关的机制，并可能解释其在精神分裂症中的作用。
Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related (hERG) potassium channel, is associated with impaired cognition, inefficient neural processing, and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation (TBS-LTP). Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.