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: 9797285
• 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/9797285
• 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; Hyperactive behavior; 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; Synapses; Synaptic Transmission; Testing; Therapeutic; Time; Vision; Woman; Work; adverse outcome; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; alcohol measurement; base; behavior test; design; 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; receptor; receptor function; symporter; synaptic function; targeted treatment; 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.

摘要