Modulation of KCC2 activity and the postnatal development of synaptic inhibition

KCC2 活性的调节和突触抑制的出生后发育

• 批准号: 10224348
• 负责人: Tarek Ziad Deeb
• 金额: $ 45.72万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224348
• 关键词: Address; Adult; Alanine; Birth; Brain; Brain-Derived Neurotrophic Factor; C-terminal; Cell surface; Cells; Childhood Neurological Disorder; Cytoplasmic Tail; Data; Development; Disease; Epilepsy; Equilibrium; Event; Exhibits; Fragile X Syndrome; Genetic; Hippocampus (Brain); Human; Hyperactivity; Impairment; Individual; Ion Channel; Ion Channel Gating; Knock-in Mouse; Knockout Mice; Lead; Ligands; Maintenance; Mediating; Membrane; Membrane Potentials; Modification; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Neurodevelopmental Disorder; Neurons; Pain Disorder; Permeability; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Process; Protein Dephosphorylation; Protein Kinase C; Proteins; Pump; Reagent; Regulation; Rett Syndrome; Rodent; Role; Scientist; Seizures; Serine; Severities; Signal Transduction; Site; Slice; Structure; Surface; Techniques; Testing; Therapeutic; Threonine; chronic painful condition; clinically significant; critical period; developmental disease; gain of function; gamma-Aminobutyric Acid; improved; in vivo; insight; mutant; nervous system disorder; neuronal excitability; novel; painful neuropathy; postnatal; postnatal development; prevent; receptor; symporter; synaptic inhibition; theories; tool; trafficking

GABAA receptors are Cl– permeable ion channels that mediate hyperpolarizing fast synaptic inhibition in the adult brain, while in immature developing neurons GABAA receptors depolarize and excite neurons. This shift in the signaling of GABAA receptors is due to the postnatal increase in the activity of KCC2, the neuron-specific K+/Cl- co-transporter. KCC2 is the major protein mechanism that allows neurons to pump Cl– out of the cell. In rodents KCC2 expression is evident at birth and increases substantially during the critical periods of early brain development between postnatal days 7 and 14. Deficits in KCC2 activity in humans lead to epilepsy, and are strongly implicated in chronic pain and developmental disorders such as Fragile X and Rett syndromes. Therefore, understanding the mechanisms by which neurons determine the proper postnatal increase of KCC2 activity and its maintenance in adults is clinically significant. KCC2 function is dynamically controlled by signals within neurons that can rapidly and reversibly modify its structure. Modification of KCC2's structure in one region increases its activity, while modification of KCC2's structure in another region decreases its activity. Our overarching hypothesis is that the correct balance between these opposing modifications contributes to the proper early postnatal development and adult maintenance of synaptic inhibition in the brain. To address this issue we have created two new genetic tools that can prevent the modification of KCC2's structure. Importantly, one of the genetic tools is the first of its kind to allow scientists to increase the function of KCC2, and so our proposal constitutes the first test of the theory which states that increasing KCC2 function can be utilized as a therapy. To date, no medications exist that can directly and rapidly increase the function of KCC2. The aims of our proposal are threefold: 1) demonstrate that preventing the modification of KCC2's structure is critical during early brain development; 2) examine the mechanisms by which disease causing factors influence the structure of KCC2 both in immature and more mature neurons; and 3) demonstrate that increasing the function of KCC2 can reduce the likelihood and severity of epileptic seizures. Our study will provide new insights on how KCC2 structure and function is controlled under normal conditions and during disease states. This information may aid in the development of new and improved treatments to alleviate the burdens of a range of neurological disorders.

GABAA受体是氯离子通道，介导成人超极化快速突触抑制 大脑，而在未成熟的发育中的神经元中，GABAA受体使神经元去极化和兴奋。中国经济的这种转变 GABAA受体的信号转导是由于神经元特异性K+/Cl-的KCC2活性在出生后增加所致 联运公司。KCC2是允许神经元将氯离子泵出细胞的主要蛋白质机制。在啮齿动物中 KCC2的表达在出生时就很明显，并在早期大脑的关键期显著增加 在出生后7天至14天之间发育。人类KCC2活性缺陷会导致癫痫，并 与慢性疼痛和发育障碍有关，如脆性X综合征和雷特综合征。 因此，了解神经元决定KCC2出生后适当增加的机制 成人的活动及其维持具有重要的临床意义。 KCC2功能是由神经元内的信号动态控制的，这些信号可以快速和可逆地改变 它的结构。在一个区域修饰KCC2的S结构使其活性增加，而在一个区域修饰KCC2的S结构使其活性增加 另一个地区的构造减少了它的活动。我们最重要的假设是，正确的平衡 这些相反的修饰有助于适当的出生后早期发育和成年后的维持 大脑中的突触抑制。为了解决这个问题，我们创造了两种新的基因工具，可以防止 KCC2的S结构的修饰。重要的是，其中一种基因工具是第一个让科学家 以增加KCC2的功能，因此我们的建议构成了对该理论的第一次考验，该理论指出 提高KCC2功能可作为一种治疗方法。到目前为止，还没有药物可以直接和快速地 增加KCC2的功能。我们建议的目的有三个：1)证明防止 KCC2的S结构的修饰在早期脑发育中起关键作用；2)研究 致病因素影响未成熟和成熟神经元中KCC2的结构； 证明增加KCC2的功能可以降低癫痫发作的可能性和严重程度。 我们的研究将为在正常情况下如何控制KCC2的结构和功能提供新的见解 在条件和疾病状态期间。这些信息可能有助于开发新的和改进的 减轻一系列神经疾病负担的治疗。