KCNH2-3.1 potassium channel and schizophrenia.

描述(申请人提供)：精神分裂症是一种使人衰弱的神经疾病，全球患病率为1%。有很强的遗传成分，估计遗传力为80%-85%。在过去的十年里，在识别精神分裂症易感基因方面取得了前所未有的进展，但单个基因的影响规模一直很小。早期的研究表明，灵长类和大脑选择性的KCNH2钾通道亚型(3.1)是与精神分裂症相关的大脑功能障碍的一个因素。然而，与KCNH2-3.1相关的关键分子、细胞和神经网络机制及其与精神分裂症发病机制的关系在很大程度上尚不清楚。最近获得了一只KCNH2-3.1亚型转基因小鼠。这项研究明确了KCNH2-3.1在精神分裂症相关皮层回路发育中的作用，并阐明了当时的关键问题 并为临床上重要的早期治疗策略和药物开发提供支持。为了验证KCNH2-3.1不仅是细胞放电模式急性变化的关键元件，而且还通过增强固有的神经元脆弱性和受损神经连接的形成而长期异常的神经生物学这一中心假设，将进行以下三个具体目标：(1)体外对具有广泛行为和认知表型的动物组织的电生理学和成像研究将确定持续神经元放电和前额叶皮质(PFC)神经元同步活动缺陷是否导致KCNH2-3.1小鼠工作记忆缺陷。前额叶神经元的持续放电和同步活动被认为反映了工作记忆功能障碍的关键细胞机制，工作记忆功能障碍被认为是精神分裂症的核心特征。(2)从具有广泛行为和认知表型的动物身上制备的体外脑片将被检测，以确定这些成年小鼠的行为缺陷是否反映了PFC和海马神经元结构可塑性的长期功能障碍。(3)遥测脑电记录、PHLOORIN分析和Inscope ix的微型活体脑成像技术将被用于确定这些小鼠的海马体和mPFC之间的神经连接是否出现选择性损伤，这也与精神分裂症有关。此外，这项工作将回答以下问题：在这些小鼠中描述的改变前额叶皮质和海马体树突棘的时间窗口是什么？抗精神病药物干预的最佳时间窗是什么？哪些细胞内信号通路参与了KCNH2-3.1介导的结构可塑性和工作记忆缺陷？这些问题的答案将确定早期治疗干预的目标，这可能是避免精神分裂症患者突触结构和行为进行性恶化的有效方法。突变KCNH2-3.1小鼠的神经回路研究对于开发基于因果关系而不是现象学的新药治疗也将是重要和必要的。

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating neurological disorder with a world-wide prevalence of 1%. There is a strong genetic component with an estimated heritability of 80-85%. In the last decade, there has been unprecedented progress in identifying schizophrenia susceptibility genes, but the effect sizes of individual genes have been meager. Earlier studies have suggested that a primate and brain selective isoform (3.1) of the KCNH2 potassium channel is a factor in the brain dysfunction associated with schizophrenia. However, the critical molecular, cellular and neural network mechanisms related to KCNH2-3.1 and their relationship to the pathogenesis of schizophrenia are largely unknown. A KCNH2-3.1 isoform transgenic mouse has recently been made. This study defines the role of KCNH2-3.1 in the development of schizophrenia related cortical circuits, and illuminates critical issues in the time course of schizophrenia and provides support for a clinically important early treatment strategy and drug development. To test the central hypothesis that KCNH2-3.1 represents a key element not only for acute changes in cell firing patterns but also for long-term aberrant neurobiology by enhancing intrinsic neuronal vulnerability and the formation of impaired neural connections, the following three specific aims will be carried out: (1) In vitro electrophysiologicl and imaging studies of tissues taken from animal with extensive behavioral and cognitive phenotype will identify whether deficits in both sustained neuronal firing and neuronal synchronized activity in the prefrontal cortex (PFC) contribute to working memory deficits in the KCNH2-3.1 mice. Neuronal sustained firing and synchronized activity in the PFC are thought to reflect the cellular mechanisms critical for working memory dysfunction, which is considered to be a core feature of schizophrenia. (2) In vitro brain slices prepared from animals with extensive behavioral and cognitive phenotypes will be examined to determine whether behavioral deficits in these mice as adults reflect long-term dysfunction of neuronal structural plasticity in the PFC and hippocampus. (3) Telemetric EEG recording, the pHluorin assay and Inscopix's miniature in vivo brain imaging technology will be applied to determine whether selective impairments in neural connections between hippocampus and mPFC develop in these mice, as has also been implicated in schizophrenia. In addition, this work will answer the following questions: what are the time window changes in altering dendritic spines of prefrontal cortex and hippocampus described in these mice? What time window is best for antipsychotic drugs intervention? Which intracellular signaling pathways are involved in KCNH2-3.1-mediated structural plasticity and working memory deficits? Answers to these questions will identify targets for early therapeutic intervention that may be an effective way to avoid progressive synaptic structural and behavioral deterioration in patients with schizophrenia. The neural circuit studies in mutant KCNH2-3.1 mice will also be important and necessary for developing new drug treatments based on causation rather than phenomenology.