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: 9976605
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976605
• 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; 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 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 Cl- 渗透性离子通道，介导成人超极化快速突触抑制 大脑中，而在未成熟的发育神经元中，GABAA 受体使神经元去极化并兴奋。这种转变在 GABAA 受体的信号传导是由于出生后 KCC2（神经元特异性 K+/Cl-）活性的增加所致 协同转运蛋白。 KCC2 是允许神经元将 Cl- 泵出细胞的主要蛋白质机制。在啮齿类动物中 KCC2 表达在出生时就很明显，并在早期大脑的关键时期大幅增加 出生后 7 至 14 天之间发育。人类 KCC2 活性缺陷会导致癫痫，并且 与慢性疼痛和发育障碍（例如脆性 X 肌瘤和雷特综合征）密切相关。 因此，了解神经元决定 KCC2 出生后适当增加的机制 成人的活性及其维持具有临床意义。 KCC2 功能由神经元内的信号动态控制，可以快速、可逆地修改 它的结构。 KCC2 某一区域结构的修饰会增加其活性，而 KCC2 的结构修饰则会增加其活性。 另一个区域的结构会降低其活性。我们的首要假设是，两者之间的正确平衡 这些相反的修饰有助于适当的产后早期发育和成年维持 大脑中的突触抑制。为了解决这个问题，我们创建了两种新的遗传工具，可以预防 KCC2结构的修改。重要的是，其中一个遗传工具是第一个允许科学家 增加 KCC2 的功能，因此我们的建议构成了对该理论的第一个检验，该理论指出： 增加 KCC2 功能可作为一种治疗方法。迄今为止，还没有任何药物可以直接、快速地 增加KCC2的功能。我们提案的目标有三个：1）证明防止 KCC2 结构的修饰在早期大脑发育过程中至关重要； 2）检查其机制 致病因素影响未成熟和较成熟神经元中 KCC2 的结构；和 3) 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KCC2结构和功能在正常情况下如何被控制提供新的见解。 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 减轻一系列神经系统疾病负担的治疗方法。