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智力低下蛋白（FMRP）的Fmr 1基因的转录沉默是智力残疾（称为脆性X综合征（FXS））的最常见遗传原因。FXS的特征还在于与自闭症和癫痫的高共发病率。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被鉴定为调节树突中局部蛋白质合成的RNA结合蛋白，并且迄今为止对FXS的研究广泛集中于FMRP在树突功能中的抑制依赖性作用。然而，尽管经过二十年的深入研究，FXS的分子基础仍然没有完全了解。 最近，我们已经确定了重要的功能FMRP超越树突状隔室，最值得注意的是FMRP在调节动作电位（AP）波形和突触传递的关键突触前作用。具体来说，我们的研究结果表明，FMRP调节神经递质释放兴奋性海马神经元通过调制AP持续时间在细胞自主突触前的方式。FMRP的这些突触前作用是不依赖于突触的，并且通过FMRP与大电导钙激活K+（BK）通道的相互作用特异性介导。FMRP的缺失导致BK通道活性降低和AP过度增宽，进而导致突触前钙内流升高，神经递质释放增加和重复活动期间的短期可塑性（STP）。基于信息论的分析表明，这些缺陷与FMRP的损失导致显着异常的能力，突触传递信息。我们的观察，FMRP调制AP持续时间在海马和皮质锥体神经元表明，BK通道依赖FMRP的突触前功能的调节可能是一个普遍的现象，可以发挥作用的病理生理FXS。事实上，我们目前的研究表明，针对BK通道功能的药理学或遗传操作可以降低癫痫发作的易感性，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然未知。拟议的研究将从单通道到行为分析，以解决这些关键问题。我们的研究结果有望为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。