A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.
A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.
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作者：
有组织的神经元放电对皮质处理至关重要，在精神分裂症中被破坏。利用人类大脑中的5 ' RACE，我们鉴定了K+通道KCNH2的灵长类特异性亚型（3.1），该亚型调节神经元放电。KCNH2-3.1 mRNA在脑中的表达水平与KCNH2-1A相当，但在心脏中的表达水平低1000倍。在精神分裂症海马中，KCNH2-3.1的表达量是KCNH2-1A的2.5倍。对5个临床样本（367个家庭，1158个不相关病例，1704个对照）的荟萃分析显示，KCNH2 snp与精神分裂症相关。与风险相关的等位基因预示着较低的智商分数和认知处理速度、与记忆相关的fMRI信号改变以及死后海马中KCNH2-3.1表达增加。KCNH2-3.1缺乏一个对缓慢通道失活至关重要的结构域。KCNH2-3.1在初级皮质神经元中的过度表达可诱导快速失活的K+电流和高频、非适应性的放电模式。这些结果确定了一个新的KCNH2通道参与皮层生理、认知和精神病，提供了一个潜在的新的心理治疗药物靶点。
Organized neuronal firing is critical for cortical processing and is disrupted in schizophrenia. Using 5’ RACE in human brain, we identified a primate-specific isoform (3.1) of the K+-channel KCNH2 that modulates neuronal firing. KCNH2-3.1 mRNA levels are comparable to KCNH2-1A in brain, but 1000-fold lower in heart. In schizophrenic hippocampus, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A. A meta-analysis of 5 clinical samples (367 families, 1158 unrelated cases, 1704 controls) shows association of SNPs in KCNH2 with schizophrenia. Risk-associated alleles predict lower IQ scores and speed of cognitive processing, altered memory-linked fMRI signals, and increased KCNH2-3.1 expression in post-mortem hippocampus. KCNH2-3.1 lacks a domain critical for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, non-adapting firing pattern. These results identify a novel KCNH2 channel involved in cortical physiology, cognition, and psychosis, providing a potential new psychotherapeutic drug target.
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