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）：氨基酸发射器GABA在整个生命周期中施加双重动作。 GABA通过GABA-A受体作用，是未成熟和发育神经元中神经元激发的主要来源。但是在成熟的神经元中，GABA是突触抑制的主要介体。最近，在新生儿发育过程中，男性与女性大脑的GABA作用的差异已被确定为性别分化的关键连接。当前的建议将这些发现扩展到包括GABA在产前脑损伤中的作用，从而增加了与认知和情感相关的残疾风险。雄性在新生儿脑损伤后遭受较差的预后，而GABA作用的激素调节可能是增加这种敏感性的变量。早产的人类婴儿因与妊娠或出生有关的创伤引起的脑损伤高风险（例如，前宾夕法尼亚，脐带绞死）或胎儿本身内神经瘤（例如，中风，癫痫发作）。通常跟随这些事件会增加细胞外GABA。该提案调查了一个新的假设，即选择性GABA-A受体激动剂外源性肌酚诱导新生大鼠海马的损害，并且可以作为早产婴儿脑损伤的模型。在未成熟的神经元中，打开GABA-A受体会导致氯化物外排，从而导致膜去极化和钙通道的开放，从而增加细胞内钙。虽然通常认为GABA受体激活和内源性钙涌入的影响是营养的，但过度钙流入是脑损伤的组成部分。当前的建议着重于表征特定目标中GABA受体激活后雌二醇对钙涌入的影响，确定了雌二醇和Muscimol对特定目标2中氯化物逆转潜力的发育变化的影响，记录了雌激素对雌激素的损害的影响，该目标对雌激素的损害构成了Huscimogen的影响，huss huscimogen的效果是huscimogen ins hymcimogen ins hymcim oscim oscim oscimogen的影响。并调查了狒狒和大鼠特定目的4的早产婴儿脑损伤的替代模型。我的长期职业目标是成为主要研究的主要学术机构的独立科学家，并对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。