THE ROLE OF BK CHANNELS IN NEUROPATHOLOGY OF FRAGILE X SYNDROME

BK 通道在脆性 X 综合征神经病理学中的作用

• 批准号: 8673062
• 负责人: Vitaly A Klyachko
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673062
• 关键词: Action Potentials; Address; Anxiety; Autistic Disorder; Behavioral; Behavioral Assay; Binding; Biochemical; Biochemistry; Calcium; Cell Culture Techniques; Cells; Cognitive; Cognitive deficits; Comorbidity; Defect; Dendrites; Dependence; Development; Electrophysiology (science); Epilepsy; Fragile X Mental Retardation Protein; Fragile X Syndrome; Functional disorder; Genes; Genetic; Goals; Hippocampus (Brain); Hyperactive behavior; Impaired cognition; Individual; Information Theory; Intellectual functioning disability; Intervention; Ion Channel; Mediating; Modeling; Molecular; Mus; Neurons; Play; Predisposition; Problem Solving; Protein Biosynthesis; Protein Fragment; Psyche structure; RNA-Binding Proteins; Regulation; Research; Role; Seizures; Slice; Social Interaction; Surface; Synapses; Synaptic Transmission; Therapeutic Intervention; Translational Regulation; Translations; Up-Regulation; base; behavior test; behavioral impairment; disability; drug development; genetic manipulation; hippocampal pyramidal neuron; in vitro Model; in vivo; insight; large-conductance calcium-activated potassium channels; mouse model; neuronal excitability; neuropathology; neurotransmitter release; novel; novel therapeutics; presynaptic; protective effect; public health relevance; research study; synaptic function; treatment strategy; voltage

DESCRIPTION (provided by applicant): Transcriptional silencing of the Fmr1 gene encoding Fragile X mental retardation protein (FMRP) is the most common inheritable cause of mental disability, known as Fragile X syndrome (FXS). FXS is also characterized by a high co-morbidity with autism and epilepsy. Extensive research efforts have thus focused on elucidating the functions of FMRP at synapses to uncover the molecular basis of FXS. FMRP was identified as an RNA-binding protein regulating local protein synthesis in dendrites, and research to date on FXS has concentrated extensively on the translation-dependent roles of FMRP in dendritic function. Yet despite two decades of intensive studies the molecular basis of FXS remains incompletely understood. We have recently identified important functions of FMRP beyond the dendritic compartment; most notably the critical presynaptic roles of FMRP in regulating action potential (AP) waveform and synaptic transmission. Specifically, our results demonstrate that FMRP regulates neurotransmitter release in excitatory hippocampal neurons via modulation of AP duration in a cell-autonomous presynaptic manner. These presynaptic actions of FMRP are translation-independent and are mediated specifically by FMRP interaction with the large-conductance calcium-activated K+ (BK) channels. Loss of FMRP causes reduced BK channel activity and excessive AP broadening, leading in turn to elevated presynaptic calcium influx, increased neurotransmitter release and short-term plasticity (STP) during repetitive activity. Information theory-based analysis indicates that these defects associated with FMRP loss cause marked abnormalities in the ability of synapses to transmit information. Our observation that FMRP modulates AP duration both in the hippocampal and cortical pyramidal neurons suggests that BK channel-dependent regulation of presynaptic function by FMRP may be a widespread phenomenon that could play a role in the pathophysiology of FXS. Indeed, our current studies suggest that pharmacological or genetic manipulations targeting BK channel function can reduce seizure susceptibility and rescue several synaptic and behavioral deficits caused by FMRP loss. Yet the mechanisms by which FMRP modulates the activity of BK channels and the roles of FMRP-BK channel interaction in cognitive and behavioral abnormalities in FXS remain unknown. The proposed studies will span from single-channel to behavioral analyses to address these critical questions. Our results are expected to provide major new insights into pathophysiology of FXS and open new avenues for drug development and intervention.

描述（由申请人提供）：编码脆性 X 型智力迟钝蛋白 (FMRP) 的 Fmr1 基因的转录沉默是导致精神残疾的最常见的遗传原因，称为脆性 X 综合征 (FXS)。 FXS 的另一个特点是与自闭症和癫痫的共病率很高。因此，广泛的研究工作集中在阐明 FMRP 在突触中的功能，以揭示 FXS 的分子基础。 FMRP 被认为是一种调节树突局部蛋白质合成的 RNA 结合蛋白，迄今为止 FXS 的研究广泛集中在 FMRP 在树突功能中的翻译依赖性作用。然而，尽管经过二十年的深入研究，FXS 的分子基础仍然不完全清楚。 我们最近发现了 FMRP 在树突室之外的重要功能；最值得注意的是 FMRP 在调节动作电位 (AP) 波形和突触传递中的关键突触前作用。具体来说，我们的结果表明，FMRP 通过以细胞自主突触前方式调节 AP 持续时间来调节兴奋性海马神经元中的神经递质释放。 FMRP 的这些突触前作用是翻译无关的，并且由 FMRP 与大电导钙激活 K+ (BK) 通道的相互作用特异性介导。 FMRP 的缺失会导致 BK 通道活性降低和 AP 过度展宽，进而导致突触前钙流入增加、神经递质释放增加以及重复活动期间的短期可塑性 (STP)。基于信息论的分析表明，这些与 FMRP 丢失相关的缺陷会导致突触传递信息的能力明显异常。我们观察到 FMRP 调节海马和皮质锥体神经元中的 AP 持续时间，这表明 FMRP 对突触前功能的 BK 通道依赖性调节可能是一种普遍现象，可能在 FXS 的病理生理学中发挥作用。事实上，我们目前的研究表明，针对 BK 通道功能的药理学或基因操作可以降低癫痫易感性，并挽救由 FMRP 丢失引起的几种突触和行为缺陷。 然而，FMRP 调节 BK 通道活性的机制以及 FMRP-BK 通道相互作用在 FXS 认知和行为异常中的作用仍不清楚。拟议的研究将从单通道到行为分析，以解决这些关键问题。我们的研究结果预计将为 FXS 的病理生理学提供重要的新见解，并为药物开发和干预开辟新途径。