KCNH2-3.1 mediates aberrant complement activation to impair hippocampal-medial prefrontal pathway associated with schizophrenia

Although elevated KCNH2-3.1 potassium channel expression is associated with cognitive dysfunctions and with schizophrenia, little is known about the pathophysiology of synapses in patient neurons and how elevated levels of KCNH2-3.1 potassium channel could lead to synaptic deficits in humans. Here, we identified specific and delayed disruption of hippocampal-mPFC synaptic transmission and connection unexpectedly associated with age-dependent reduction of SERPING1, CFH and CD74 in the KCNH2-3.1 overexpression transgenic mice, and dysfunctional interactions between hippocampus and prefrontal cortex in the fMRI coupling signal during working memory encoding in healthy subjects carrying schizophrenia-associated risk alleles of KCNH2 potassium channel. These three genes are enriched in neurons or microglia, and reduced expression of these genes dysregulates the complement cascade activation underlying impaired synaptic connectivity of hippocampal-mPFC projections. Knockdown of these genes' expression impairs synapse formation, and replenishing reduced CFH gene expression rescues KCNH2-3.1-induced impaired synaptogenesis. Our results uncover a previously unrecognized role of truncated KCNH2-3.1 potassium channel mediating reduced expression of three genes mentioned above, which enhances aberrant complement cascade activation during development. These results direct an important conceptual advance that truncated KCNH2-3.1 causes synapse loss mediated by abnormally activated complement system, rather than aberrant neuronal firing, may represent the therapeutic targets for a number of patients with schizophrenia. Overall design: In this study, we employed multifaceted approaches to investigate whether there are impaired functional or/and structural connectivity between the hippocampus and the PFC with schizophrenia-like behavior deficits in a transgenic KCNH2-3.1 mouse model and human subjects with schizophrenia-associated risk-alleles in KCNH2, and what molecular mechanisms of hippocampus-PFC disruption are in the transgenic KCNH2-3.1 mice.

尽管KCNH2-3.1钾通道（KCNH2-3.1 potassium channel）表达上调与认知功能障碍及精神分裂症密切相关，但目前对患者神经元突触的病理生理学机制，以及KCNH2-3.1钾通道表达升高如何导致人类突触功能缺陷的过程仍知之甚少。
本研究中，我们在KCNH2-3.1过表达转基因小鼠中，意外发现了与SERPING1、CFH及CD74随年龄下调相关的特异性、迟发性海马-内侧前额叶皮层（hippocampal-mPFC）突触传递与连接异常；同时在携带精神分裂症相关KCNH2钾通道风险等位基因的健康受试者中，观察到工作记忆编码阶段功能磁共振成像（fMRI）耦合信号中海马与前额叶皮层间的交互功能失调。
上述三个基因在神经元或小胶质细胞中富集，其表达下调会扰乱补体级联激活过程，而该过程正是海马-内侧前额叶皮层投射突触连接受损的核心机制。
敲低这三个基因的表达会损害突触形成，而补充下调的CFH基因表达则可挽救KCNH2-3.1诱导的突触发生缺陷。
本研究结果揭示了截短型KCNH2-3.1钾通道此前未被认知的作用：它可介导上述三个基因的表达下调，进而在发育过程中加剧异常的补体级联激活。
本研究结果带来了重要的概念性进展：截短型KCNH2-3.1通过异常激活的补体系统介导突触丢失，而非异常神经元放电，这一机制或可成为众多精神分裂症患者的治疗靶点。
研究整体设计：本研究采用多维度研究方法，旨在探究KCNH2-3.1转基因小鼠模型以及携带KCNH2精神分裂症相关风险等位基因的人类受试者中，是否存在伴随精神分裂症样行为缺陷的海马与前额叶皮层（PFC）功能及/或结构连接受损，并解析KCNH2-3.1转基因小鼠中海马-前额叶皮层连接破坏的分子机制。