Novel GABA Actions on the Developing Brain

GABA 对大脑发育的新作用

• 批准号: 7013499
• 负责人: JOSEPH Luis NUNEZ
• 金额: $ 13.68万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013499
• 关键词: GABA receptor; NMDA receptors; baboons; behavior test; brain injury; calcium flux; developmental neurobiology; electrophysiology; estradiol; hippocampus; laboratory rat; molecular pathology; muscimol; receptor expression; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): The amino acid transmitter GABA exerts a dual action across the life span. Acting via the GABA-A receptor, GABA is a major source of neuronal excitation in immature and developing neurons. But in mature neurons, GABA is the predominant mediator of synaptic inhibition. Divergence in GABA action in the male versus female brain during neonatal development has recently been identified as a critical junction in sexual differentiation. The current proposal extends these findings to include a role for GABA in prenatal brain damage, increasing the risk of disabilities associated with cognition and affect. Males suffer worse outcomes following neonatal brain damage, and hormonal modulation of GABA action may be a contributing variable to this increased susceptibility. Preterm human infants are at high risk for brain injury resulting from trauma related to pregnancy or birth (e.g. pre-eclampsia, strangulation by the umbilical cord) or neurotrauma within the fetus itself (e.g. stroke, seizures). Often following these events there is an increase in extracellular levels of GABA. This proposal investigates the novel hypothesis that exogenous muscimol, a selective GABA-A receptor agonist, induces damage in the newborn rat hippocampus, and may serve as a model of preterm human infant brain damage. In immature neurons, opening GABA-A receptors causes chloride efflux, resulting in membrane depolarization and opening of calcium channels, thereby increasing intracellular calcium. While the effect of GABA receptor activation and endogenous calcium influx during development are generally considered to be trophic, excessive calcium influx is an integral component of brain injury. The current proposal focuses on characterizing the effect of estradiol pretreatment on calcium influx following GABA receptor activation in Specific Aim 1, determining the effect of estradiol and muscimol on the developmental change in the reversal potential for chloride in Specific Aim 2, documenting the effect of an estradiol isomer that binds with low affinity to the estrogen receptor on muscimol-induced hippocampal damage in Specific Aim 3, and investigating alternative models of preterm infant brain injury in the baboon and rat in Specific Aim 4. My long-term career goals are to become an independent scientist at a major research-oriented academic institution, and to make important contributions to the field of pediatric neurology. I intend to pursue this research in a laboratory of my own.

描述（由申请人提供）：氨基酸递质 GABA 在整个生命周期中发挥双重作用。 GABA 通过 GABA-A 受体发挥作用，是未成熟和发育中神经元神经元兴奋的主要来源。但在成熟神经元中，GABA 是突触抑制的主要介质。最近，新生儿发育过程中男性和女性大脑中 GABA 作用的差异最近被认为是性别分化的关键连接点。目前的提案扩展了这些发现，包括 GABA 在产前脑损伤中的作用，增加了与认知和情感相关的残疾风险。男性在新生儿脑损伤后会遭受更严重的后果，而 GABA 作用的激素调节可能是导致易感性增加的一个因素。早产儿因怀孕或分娩相关的创伤（例如先兆子痫、脐带勒窄）或胎儿本身的神经创伤（例如中风、癫痫）而导致脑损伤的风险很高。通常在这些事件发生后，细胞外的 GABA 水平会增加。该提案研究了一种新假设，即外源性蝇蕈醇（一种选择性 GABA-A 受体激动剂）会诱导新生大鼠海马体损伤，并可能作为人类早产婴儿脑损伤的模型。在未成熟的神经元中，打开 GABA-A 受体会导致氯离子外流，导致膜去极化和钙通道开放，从而增加细胞内钙。虽然发育过程中 GABA 受体激活和内源性钙流入的影响通常被认为是营养性的，但过量的钙流入是脑损伤的一个组成部分。当前提案的重点是表征特定目标 1 中 GABA 受体激活后雌二醇预处理对钙流入的影响，确定特定目标 2 中雌二醇和蝇蕈醇对氯逆转电位发育变化的影响，记录雌二醇异构体与雌激素受体以低亲和力结合，对特定目标 3 中蝇蕈醇诱导的海马损伤进行研究，并研究早产的替代模型具体目标 4 中狒狒和大鼠的婴儿脑损伤。我的长期职业目标是成为主要研究型学术机构的独立科学家，并为儿科神经病学领域做出重要贡献。我打算在自己的实验室中进行这项研究。