Alcohol and GABAergic Transmission in the Developing Neocortex

发育中的新皮质中的酒精和 GABA 能传递

基本信息

批准号：
7413965
负责人：
Jennifer Sanderson
金额：
$ 1.25万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413965
关键词：
Action Potentials Acute Affect Agonist Alcohol consumption Alcohols Animals Apoptotic Benzodiazepines Brain Cell Death Cells Cessation of life Chromosome Pairing Confocal Microscopy Congenital Abnormality Data Development Diazepam Electric Stimulation Ethanol Exposure to Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome Figs - dietary Gated Ion Channel Glutamates Hippocampus (Brain)Hour Image Imaging Techniques Incidence Interneurons Laboratories Lead Learning Ligands Literature Live Birth Longitudinal Studies Measures Mediating Membrane Potentials Memory impairment Methods Neocortex Neonatal Neonatal Alcohol Exposure Nerve Degeneration Neuraxis Neurons Neurotransmitters Patch-Clamp Techniques Patient currently pregnant Personal Satisfaction Phenobarbital Physiologic pulse Population Psyche structure Pulse taking Range Rattus Reporting Rest Silver Staining Somatosensory Cortex Synapses Synaptic Transmission Techniques Testing Therapeutic Intervention Thinking Tissue Stains United States Work alcohol abstinence alcohol exposure base disability gamma-Aminobutyric Acid hippocampal pyramidal neuron neocortical neonate neuron loss neuronal excitability novel therapeutics postsynaptic presynaptic prevent protein expression research study response somatosensory symporter transmission process

项目摘要

DESCRIPTION (provided by applicant): Fetal alcohol syndrome (FAS) continues to be one of the leading causes of birth defects. Although it is preventable by abstaining from alcohol consumption while pregnant, the estimated incidence for FAS in the United States is 0.2 to 1.0 per 1000 live births. Currently there are no preventable treatments for FAS. It is well characterized that ethanol exposure during development affects the central nervous system ranging from subtle structural and functional alterations to widespread neuronal death. Following ethanol (EtOH) exposure, the mechanism as to how it causes widespread neuronal degeneration is not well characterized. It has been postulated that EtOH-induced cell death results from excessive inhibition of neuronal activity in the developing neocortex. EtOH has been thought to act like a benzodiazepine by enhancing GABAARs postsynaptically. However, previous work from our laboratory suggests that EtOH increases neuronal excitability, by increasing GABA release. I hypothesize that EtOH increases GABA release leading to excitation of neurons in cortical layers that undergo apoptotic cell death in response to EtOH exposure (layers II and IV) but not in layers that do not (i.e. layer III). In specific aim #1, I will use a combination of whole-cell and perforated patch-electrophysiological techniques to determine if EtOH is differentially affecting GABAergic transmission in layers INV of the neonatal somatosensory cortex. In specific aim #2, I will determine if activation of the GABAAR results in excitation in the same neuronal layers by using a combination of loose cell-attached electrophysiological and Ca2+ imaging techniques. If I determine that there is an increase in excitability of the target cell, I will then determine if EtOH increases excitability by increasing action potential-dependent GABA release. In the long-term, these studies might form the basis for the development of novel therapeutic interventions against FAS that target the excitatory actions of GABAARs in immature neurons. Lay summary: Fetal alcohol exposure is a common cause of mental disabilities in the U.S. The mechanism by which alcohol damages the developing brain are poorly characterized. The studies proposed here will increase our understanding of how alcohol affects the actions of the neurotransmitter GABA and in the long term might form the basis for the developmental treatments against this problem.

描述（由申请人提供）：胎儿酒精综合症（FAS）仍然是出生缺陷的主要原因之一。尽管怀孕期间戒酒可以预防 FAS，但在美国，FAS 的发病率估计为每 1000 名活产儿 0.2 至 1.0 例。目前 FAS 尚无可预防的治疗方法。众所周知，发育过程中接触乙醇会影响中枢神经系统，从细微的结构和功能改变到广泛的神经元死亡。接触乙醇 (EtOH) 后，其如何导致广泛的神经元变性的机制尚不清楚。据推测，乙醇诱导的细胞死亡是由于过度抑制正在发育的新皮质中的神经元活动所致。人们认为乙醇的作用类似于苯二氮卓类药物，通过增强突触后的 GABAAR 来发挥作用。然而，我们实验室之前的研究表明，EtOH 通过增加 GABA 的释放来增加神经元的兴奋性。我假设 EtOH 会增加 GABA 的释放，导致皮质层中的神经元兴奋，这些神经元响应 EtOH 暴露而发生细胞凋亡（第 II 层和第 IV 层），但在没有暴露的皮质层（即第 III 层）中则不会。在具体目标#1中，我将结合使用全细胞和穿孔贴片电生理技术来确定EtOH是否对新生儿体感皮层INV层中的GABA能传输产生差异性影响。在具体目标#2中，我将结合使用松散细胞附着的电生理学和 Ca2+ 成像技术来确定 GABAAR 的激活是否会导致相同神经元层的兴奋。如果我确定靶细胞的兴奋性增加，我将确定 EtOH 是否通过增加动作电位依赖性 GABA 释放来增加兴奋性。从长远来看，这些研究可能为开发针对 FAS 的新型治疗干预措施奠定基础，这些干预措施以 GABAAR 在未成熟神经元中的兴奋作用为目标。简单总结：胎儿酒精暴露是美国精神残疾的常见原因。酒精损害发育中大脑的机制尚不清楚。这里提出的研究将加深我们对酒精如何影响神经递质 GABA 作用的理解，从长远来看，可能会成为针对这一问题的开发治疗的基础。