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

基本信息

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
项目类别：
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

项目摘要

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，在未成熟的发育神经元中，GABAA 受体会去极化并兴奋神经元。 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 KCC2 是啮齿动物中神经元将 Cl- 泵出细胞的主要蛋白质机制。 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（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 KCC2 某一区域结构的改变会增加其活性，而 KCC2 的结构改变则会增加其活性。我们的首要假设是，另一个区域的结构会降低其活性。这些竞争性修饰有助于适当的产后早期发育和成年维持为了解决这个问题，我们创造了两种可以预防大脑突触抑制的新遗传工具。重要的是，其中一个遗传工具是第一个允许科学家进行的。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：迄今为止，还没有可以直接、快速地利用增加KCC2功能的药物来治疗。增加 KCC2 的功能我们提案的目的有三个：1）证明可以防止 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的 KCC2 结构；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。这些信息可能有助于开发新的和改进的方法。减轻一系列神经系统疾病负担的治疗方法。