The chloride cotransporter NKCC1 in the embryonic etiology and treatment of FASD

氯协同转运蛋白 NKCC1 在 FASD 胚胎病因学和治疗中的作用

• 批准号: 10675600
• 负责人: Hermes H Yeh
• 金额: $ 50.31万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675600
• 关键词: Abstinence; Acceleration; Acute; Address; Affect; Alcohol consumption; Alcohols; Attention; Automobile Driving; Behavioral; Bumetanide; Child; Chlorides; Cognitive; Companions; Consumption; Control Groups; Counseling; Defect; Electrophysiology (science); Embryo; Embryonic Development; Environment; Equilibrium; Ethanol; Etiology; FDA approved; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Future; Glutamates; Height; Homeostasis; Hyperactivity; Impairment; Individual; Interneurons; Intervention; Investigation; Knowledge; Label; Life; Light; Longevity; Medial; Mediating; Membrane Potentials; Molecular; Mothers; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuroanatomy; Neurons; Neurotransmitter Receptor; Outcome; Perforation; Personal Satisfaction; Pharmaceutical Preparations; Play; Prefrontal Cortex; Pregnancy; Pregnant Women; Prevention; Process; Protein Isoforms; Public Health; Recording of previous events; Regimen; Research; Research Project Grants; Rest; Reversal Learning; Slice; Strategic Planning; Strategic vision; Synapses; Synaptic Transmission; Testing; Therapeutic; Time; Woman; Work; adverse outcome; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; alcohol measurement; antagonist; behavior test; cell motility; experience; experimental study; flexibility; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in utero; innovation; male; migration; neurobehavior; neurobehavioral; neurobehavioral test; neurotransmission; novel; offspring; outreach; pharmacologic; postnatal; prenatal exposure; prenatal therapy; prevent; rational design; receptor; receptor function; symporter; synaptic function; targeted treatment; translational potential; treatment strategy; young adult

ABSTRACT Preventable as it is by abstinence during pregnancy, maternal ethanol consumption is a significant public health concern because a significant percentage of pregnant women drink; some even binge drink to risky levels. Consumption of ethanol during pregnancy can lead to fetal alcohol spectrum disorders (FASD), hallmarked by life- long neurobehavioral and cognitive abnormalities in the offspring. Indeed, children with history of having been exposed in utero to even moderate levels of ethanol frequently present with varying degrees of deleterious neurobehavioral and cognitive outcomes. Yet, effective targeted treatment strategies for FASD/FAS are lacking or ill defined. The overarching impetus driving this research project is that a better understanding of the cellular and molecular underpinnings of FASD-associated abnormalities is needed. To this end, we will test a novel mechanistic hypothesis that ethanol disrupts chloride homeostasis in embryonic neurons, and propose to assess the therapeutic potential of targeting chloride co-transporters in order to develop and advance strategies for the pharmacological intervention of FASD in utero. Specific Aim 1: Test the hypothesis that blocking the function of NKCC1 with its antagonist bumetanide prevents and/or rescues ethanol’s effect on chloride homoeostasis in migrating embryonic GABAergic cortical interneurons and mitigates their abnormal tangential migration due to ethanol exposure in utero. Specific Aim 2: Test the hypothesis that bumetanide treatment prevents and/or rescues the impaired mPFC- dependent behavioral flexibility and attentional capacity in young adult mice exposed in utero to ethanol. Specific Aim 3: Test the hypothesis that bumetanide treatment prevents and/or rescues the (1) altered number and/or distribution of GABAergic cortical interneurons and/or (2) abnormal GABAergic and glutamatergic neurotransmission in the mPFC of young adult mice exposed in utero to ethanol. Our previous work established that GABA promotes the tangential migration of GABAergic cortical interneurons, and that ethanol affects this process to result in an “interneuronopathy” with enduring adverse consequences on cortical form, synaptic function and neurobehavior. However, the mechanism underlying this interneuronopathy is not known. The three specific aims will fill this knowledge gap and, in so doing, advance our understanding of the etiology underlying FASD. Overall, for the first time, NKCC1 will be investigated as a key unifying mechanism underlying the untoward effects of ethanol exposure in utero on tangential migration, chloride homeostasis and long- term neurobehavioral and cognitive outcomes, and pharmacologically targeted as potential therapy for FASD. In this light, this proposal addresses pressing questions in FASD that are highly significant, taking a multi-level neuroanatomical, electrophysiological and behavioral approach that is innovative, impactful, with great potential for shedding light on the therapeutic management of FASD.

摘要 尽管孕期禁酒是可以预防的，但孕妇饮酒是一种重大的公共健康 令人担忧的是，相当大比例的孕妇饮酒；有些人甚至狂饮到危险的程度。 怀孕期间饮用酒精会导致胎儿酒精谱系障碍(FASD)，其特点是生活- 子代长期的神经行为和认知异常。事实上，有过往经历的儿童 在子宫内暴露在中等水平的乙醇中经常会出现不同程度的有害 神经行为和认知结果。然而，对于FASD/Fas缺乏有效的靶向治疗策略或有病 已定义。推动这一研究项目的主要动力是更好地理解细胞和 FASD相关异常的分子基础是必要的。为此，我们将测试一种新颖的机械装置 假设乙醇破坏胚胎神经元中氯的动态平衡，并建议评估治疗 以氯离子共转运体为靶点的潜力，以开发和推进药理研究策略 宫内FASD的干预。 特定目标1：验证用其拮抗剂布美他尼阻断NKCC1功能防止 和/或挽救乙醇对迁移的胚胎GABA能皮质中间神经元氯离子稳态的影响 并减轻子宫内乙醇暴露引起的异常切向迁移。 具体目标2：测试布美他尼治疗预防和/或挽救受损的mPFC- 子宫内酒精暴露的年轻成年小鼠的依赖行为灵活性和注意力能力。 具体目标3：测试布美他尼治疗预防和/或挽救(1)改变的数字的假设 和/或GABA能皮质中间神经元和/或(2)GABA能和谷氨酸能异常 子宫内暴露于乙醇的成年幼鼠mPFC的神经传递。 我们以前的工作证实了GABA促进GABA能皮层中间神经元的切向迁移， 乙醇会影响这一过程，导致“神经元间病变”，并对 皮质形态、突触功能和神经行为。然而，这种神经元间病变的机制是 不知道。这三个具体目标将填补这一知识空白，并通过这样做，促进我们对 FASD的病因学基础。总体而言，将首次将NKCC1作为关键的统一机制进行调查 子宫内酒精暴露对切向迁移、氯离子动态平衡和长时间内环境的不良影响 术语神经行为和认知结果，以及药理学目标作为FASD的潜在治疗方法。在这 轻，这项建议解决了FASD中非常重要的紧迫问题，采取了多个层面 神经解剖、电生理和行为方法是创新的、有影响的、具有巨大潜力的 为FASD的治疗提供了新的思路。