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: 9442951
• 负责人: Tarek Ziad Deeb
• 金额: $ 48.42万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9442951
• 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; Gated Ion Channel; Genetic; Hippocampus (Brain); Human; Hyperactive behavior; 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 pain; 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; 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受体是一种Cl-渗透性离子通道，在成人中介导超极化快速突触抑制 大脑中，而在未成熟的发育中的神经元GABAA受体去兴奋和兴奋神经元。的这种转变 GABAA受体的信号传导是由于出生后KCC 2活性的增加，神经元特异性K+/Cl- 协同转运体KCC 2是允许神经元将Cl-泵出细胞的主要蛋白质机制。在啮齿动物中 KCC 2的表达在出生时是明显的，并且在早期脑发育的关键时期显著增加。 出生后第7至14天的发育。人类KCC 2活性的缺陷导致癫痫， 与慢性疼痛和发育障碍如脆性X染色体和Rett综合征密切相关。 因此，了解神经元决定出生后KCC 2适当增加的机制， 活性及其在成人中的维持具有临床意义。 KCC 2的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KCC 2的功能。 它的结构。KCC 2一个区域结构的修饰可以增加其活性，而KCC 2的修饰可以增加其活性 另一个区域的结构会降低其活性。我们的首要假设是， 这些相反的修饰有助于出生后早期的正常发育和成年后的 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遗传工具， KCC 2的结构修饰。重要的是，其中一种遗传工具是第一种允许科学家 增加KCC 2的功能，因此我们的建议构成了对该理论的第一次测试，该理论指出， 增加KCC 2功能可用作治疗。到目前为止，还没有药物可以直接和快速地 增加KCC 2的功能。我们的建议有三个目的：1）证明防止 KCC 2结构的改变在早期大脑发育过程中至关重要; 2）研究KCC 2结构改变的机制， 致病因素影响KCC 2在未成熟和更成熟神经元中的结构;以及3） 研究表明，增加KCC 2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KCC 2的结构和功能在正常情况下如何控制提供新的见解。 在疾病状态下和疾病状态下。这些信息可能有助于开发新的和改进的 治疗以减轻一系列神经系统疾病的负担。