Alcohol and Developing Neuronal Circuits

酒精与发育中的神经元回路

• 批准号: 7589823
• 负责人: Carlos Fernando Valenzuela
• 金额: $ 24.89万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 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 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589823
• 关键词: AMPA Receptors; Action Potentials; Acute; Address; Affect; Alcohols; Axon; Brain region; Brain-Derived Neurotrophic Factor; Breathing; Cessation of life; Cognitive; Data; Development; Doctor of Medicine; Doctor of Philosophy; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Ethanol; Event; Exposure to; Fetal Alcohol Exposure; Figs - dietary; Frequencies; Generations; Glutamates; Hippocampus (Brain); Hour; Image; Imaging Techniques; Immunohistochemistry; Impaired cognition; In Vitro; Interneurons; Lead; Learning; Life; Link; Measures; Mediating; Memory; Neonatal; Neurons; Outcome; Patch-Clamp Techniques; Pattern; Physiologic pulse; Preparation; Probability; Proteins; Pyramidal Cells; Rattus; Recurrence; Research Personnel; Rodent; Scheme; Secondary to; Slice; Source; Synapses; Techniques; Testing; Time; Western Blotting; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; mature animal; memory process; mossy fiber; neuronal growth; novel; patch clamp; postsynaptic; presynaptic; programs; receptor; symporter; synaptogenesis; transmission process; voltage; voltage gated channel

DESCRIPTION (provided by applicant): Fetal alcohol exposure results in persistent cognitive dysfunctions that may be secondary to damage of the hippocampus, a brain region involved in learning and memory. During development, the hippocampus displays a pattern of network-driven neuronal activity known as giant depolarizing potentials (GDPs). These events are mediated, in part, by GABAA receptors, which are depolarizing in immature neurons that express low levels of the Cl exporter, KCC2, and thus, have higher [Cl]i. Preliminary data indicates that ethanol (EtOH) potently increases the frequency of GDPs and that the underlying mechanism of this effect is an increase in the probability of GABA and glutamate release at interneurons. We hypothesize that EtOH increases transmitter release at mossy fibers, which can co-release GABA and glutamate in the developing hippocampus. Alternatively, GABA could be released from interneurons terminals and glutamate from pyramidal neuronal terminals. Moreover, we hypothesize that the EtOH-induced increase of GDP frequency will result in an elevation of [CA2+]i, which will lead to downregulation of KCC2 via an increase in BDNF levels, resulting in a delayed switch in the actions of GABAA receptors from excitatory to inhibitory. Specific Aim #1 is to determine the source of the EtOH-induced increase in GABA and glutamate. Using patch-clamp electrophyisiological techniques and neonatal hippocampal slices, we will measure paired-pulse plasticity of GABAA and AMPA receptor-mediated postsynaptic currents evoked in CA3 interneurons by stimulation of mossy fibers, internuerons, or pyramidal cells. Specific Aim #2 is to determine if the EtOH-induced increase of GDP frequency elevates [CA2+]i. We propose to use CA2+ imaging and patch-clamp techniques to address this possibilty and will also investigate the effect of EtOH on the degree of synchronization of developing neuronal ensembles. Specific Aim #3 is to assess whether EtOH modulation of GDPs affects KCC2 levels in vitro. We will also investigate the effect of EtOH on BDNF and pCREB levels. Specific Aim #4 is to determine the impact of long-term EtOH exposure in vivo on GDP-driven network activity and KCC2 levels. We will expose neonatal rats along their dams to EtOH via inhalation chambers and measure expression of KCC2 levels and the switch in the actions of GABAA receptors from excitatory to inhibitory. We will also investigate whether in vivo EtOH exposure induces alterations in synchronized neuronal activity. Collectively, these studies will establish that network neuronal activity driven by the excitatory actions of GABAA is a novel and important target of the actions of EtOH during hippocampal development.

描述（由申请人提供）：胎儿酒精暴露导致持续的认知功能障碍，可能继发于海马体损伤，海马体是参与学习和记忆的大脑区域。在发育过程中，海马体显示出一种被称为巨大去极化电位（gdp）的网络驱动的神经元活动模式。这些事件在一定程度上是由GABAA受体介导的，GABAA受体在未成熟神经元中去极化，表达低水平的Cl输出物KCC2，因此具有较高的[Cl]i。初步数据表明，乙醇（EtOH）能有效地增加GDPs的频率，这种效应的潜在机制是增加中间神经元释放GABA和谷氨酸的可能性。我们假设EtOH增加苔藓纤维的递质释放，这可以在发育中的海马中共同释放GABA和谷氨酸。或者，GABA可以从中间神经元末端释放，谷氨酸可以从锥体神经元末端释放。此外，我们假设etoh诱导的GDP频率增加将导致[CA2+]i的升高，这将通过BDNF水平的增加导致KCC2的下调，从而导致GABAA受体从兴奋性到抑制性作用的延迟转换。具体目的1是确定etoh诱导的GABA和谷氨酸增加的来源。