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: 10459318
• 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/10459318
• 关键词: Abstinence; Acute; Address; Affect; Alcohol consumption; Alcohols; Attention; Automobile Driving; Behavioral; Bumetanide; Cells; 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; Lead; Life; Light; Longevity; Medial; Mediating; Membrane Potentials; Molecular; Mothers; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurotransmitter Receptor; Outcome; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology; 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; base; behavior test; experience; experimental study; flexibility; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in utero; innovation; male; migration; neurobehavior; neurobehavioral; neurobehavioral test; neurotransmission; novel; offspring; outreach; postnatal; prenatal exposure; prenatal therapy; prevent; rational design; receptor; receptor function; symporter; synaptic function; targeted treatment; translational potential; transmission process; 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.

抽象的 由于孕期禁酒可以预防孕产期乙醇消费，因此它是一个重要的公共卫生问题 由于很大比例的孕妇饮酒而引起关注；有些人甚至酗酒到危险程度。 怀孕期间摄入乙醇会导致胎儿酒精谱系障碍 (FASD)，其特点是生命- 后代的长期神经行为和认知异常。确实，有过这样经历的孩子 在子宫内接触即使是中等水平的乙醇也经常会产生不同程度的有害物质 神经行为和认知结果。然而，针对 FASD/FAS 的有效靶向治疗策略缺乏或不佳 定义的。推动该研究项目的首要动力是更好地了解细胞和 需要 FASD 相关异常的分子基础。为此，我们将测试一种新颖的机制 假设乙醇会破坏胚胎神经元中的氯稳态，并建议评估其治疗效果 靶向氯协同转运蛋白的潜力，以制定和推进药理学策略 FASD 的子宫内干预。 具体目标 1：检验用其拮抗剂布美他尼阻断 NKCC1 功能可预防的假设 和/或挽救乙醇对迁移胚胎 GABA 能皮质中间神经元中氯离子稳态的影响 并减轻由于子宫内乙醇暴露而导致的异常切向迁移。 具体目标 2：检验布美他尼治疗可预防和/或挽救受损的 mPFC 的假设 子宫内暴露于乙醇的年轻成年小鼠的依赖性行为灵活性和注意力能力。 具体目标 3：检验布美他尼治疗可预防和/或挽救 (1) 数量改变的假设 和/或 GABA 能皮质中间神经元的分布和/或 (2) 异常的 GABA 能和谷氨酸能 子宫内暴露于乙醇的年轻成年小鼠 mPFC 中的神经传递。 我们之前的工作证实 GABA 促进 GABA 能皮质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”，并对人体产生持久的不良后果 皮质形式、突触功能和神经行为。然而，这种中间神经元病的潜在机制是 不知道。这三个具体目标将填补这一知识空白，从而增进我们对 FASD 的病因学。总体而言，NKCC1 将首次作为关键统一机制进行研究 子宫内乙醇暴露对切向迁移、氯离子稳态和长期 术语神经行为和认知结果，以及药物靶向作为 FASD 的潜在治疗方法。在这个 光，该提案解决了 FASD 中非常重要的紧迫问题，采取了多层次的方法 神经解剖学、电生理学和行为学方法，具有创新性、影响力，具有巨大的潜力 阐明 FASD 的治疗管理。