权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of Kainate Receptors on Modulation of Synaptic Transmission and Seizure Susceptibility to Hypoxia in Neonatal Mice

红藻氨酸受体对新生小鼠突触传递和缺氧癫痫易感性调节的作用

基本信息

批准号：
9339744
负责人：
Santina Agnes Zanelli
金额：
$ 19.75万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9339744
关键词：
Acids Acute Address Adult Agreement Algorithms Apoptosis Area Asphyxia Benchmarking Brain Brain Hypoxia-Ischemia Cells Clinical Consensus Data Development Diagnosis Disease Electrophysiology (science)Embryo Epilepsy Exposure to Frequencies Functional disorder Generations Glucose Glutamate Receptor Glutamates Goals Hippocampus (Brain)Hypoxia In Vitro Incidence Injection of therapeutic agent Interneurons Ischemia Kainic Acid Receptors Kinetics Knock-out Knowledge Lead Life Measures Mediating Microscopy Mission Modeling Mus National Institute of Neurological Disorders and Stroke Neonatal Neurons Neuropsychology Neurotoxins Newborn Animals Oxygen Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase Play Predisposition Process Rattus Receptor Activation Regulation Research Role Seizures Signal Transduction Slice Status Epilepticus Synapses Synaptic Transmission Techniques Temporal Lobe Epilepsy Testing Time Transgenic Mice Wild Type Mouse base deprivation differential expression excitotoxicity experimental study gamma-Aminobutyric Acid hippocampal pyramidal neuron improved in vitro Model in vivo juvenile animal kainate mature animal neonatal brain neonate neuronal excitability neurotransmitter release new therapeutic target novel patch clamp postnatal prevent receptor receptor function response two-photon

项目摘要

PROJECT SUMMARY Seizures in neonates are a vexing clinical problem with lack of consensus on diagnosis and treatment goals. The problem is further compounded by the disappointing efficacy of currently available anti-seizure drugs. The lack of progress in improving treatment algorithms for these patients is partly due to an incomplete understanding of the mechanisms underlying seizure generation in an immature brain. While a large amount of research has focused on excitatory to inhibitory synaptic transmission imbalance, the knowledge gained in this area has failed to lead to more effective or safer therapies for neonates with seizures. Kainate receptors are a class of receptors mediating excitation in the brain that have recently been the subject of increased scrutiny for their role in the pathophysiology of seizures. They are abundantly expressed in the brain of neonatal animals and have diverse functions important to the regulation of neuronal network activity. Gaps in knowledge remain in the understanding of their role in modulating response to hypoxia and seizure generation in the neonatal period. Our preliminary data suggest that activation of kainate receptors during hypoxia enhances excitatory and decreases inhibitory synaptic transmission in neonatal mice. Further, pre-treatment with a kainate receptor antagonist decreases susceptibility to hypoxic seizures in these mice. In this proposal we aim to expand on this preliminary data and further characterize the role of these receptors in modulating susceptibility to hypoxic seizures in neonatal mice by testing the hypothesis that activation of kainate receptors by glutamate during hypoxia alters synaptic transmission leading to increased seizure susceptibility in the neonatal mouse. To address this question, we will first characterize kainate receptor-mediated modulation of excitatory and inhibitory synaptic transmission during hypoxia using patch-clamp electrophysiology techniques in wild-type and GluK-2 knockout neonatal mice (Aim 1). We will then investigate the role of kainate receptor on seizure susceptibility following hypoxia in wild-type and GluK2 knockout neonatal mice. The effects of hypoxia on neuronal activation in the neonatal mouse hippocampus will also be evaluated using the Ca++ indicator GCaMP6 (Aim 2). Relevance to the mission of the agency: The proposed studies will further our understanding of the role kainate receptor in the pathophysiology of early-life seizures and may help delineate novel therapeutic targets. Results from these studies will advance our understanding of the epileptogenic process involved with epilepsies of neurodevelopmental origins, a goal highlighted in the consensus-derived NINDS “2014 Benchmarks for Epilepsy Research” statement.

项目摘要新生儿癫痫发作是一个令人烦恼的临床问题，缺乏共识的诊断和治疗目标。目前可用的抗癫痫药物的效果令人失望，使问题进一步复杂化。的在改善这些患者的治疗算法方面缺乏进展，部分原因是对这些患者的认识不全面，未成熟大脑癫痫发作的潜在机制虽然大量的研究集中在兴奋性到抑制性突触传递的不平衡，在这一领域获得的知识已经失败从而为癫痫发作的新生儿提供更有效或更安全的治疗。红藻氨酸受体是一类调节大脑中的兴奋，最近已经成为越来越多的审查的主题，因为它们在大脑中的作用。癫痫的病理生理学它们在新生动物的脑中大量表达，并且具有多样性。对调节神经元网络活动具有重要作用。知识上的差距仍然存在于对它们在新生儿期调节缺氧反应和癫痫发作中的作用。我们的初步数据表明，在缺氧时红藻氨酸受体的激活增强了兴奋性，降低新生小鼠的抑制性突触传递。此外，用红藻氨酸受体预处理拮抗剂降低了这些小鼠对缺氧性癫痫发作的易感性。在本提案中，我们旨在扩大这一点初步数据，并进一步表征这些受体在调节缺氧易感性中的作用癫痫发作的新生小鼠通过测试的假设，红藻氨酸受体的激活谷氨酸在缺氧改变突触传递，导致新生小鼠癫痫发作易感性增加。为了解决这个问题，我们将首先描述红藻氨酸受体介导的兴奋性和用膜片钳电生理技术在野生型和 GluK-2敲除新生小鼠（Aim 1）。我们将探讨红藻氨酸受体在癫痫发作中的作用野生型和GluK 2敲除新生小鼠缺氧后的易感性。缺氧对还将使用Ca++指示剂GCaMP 6评价新生小鼠海马中的神经元活化 (Aim 2）。与该机构使命的相关性：拟议的研究将进一步加深我们对该机构作用的理解。红藻氨酸受体在早期癫痫发作的病理生理学中的作用，并可能有助于描绘新的治疗靶点。这些研究结果将促进我们对癫痫发生过程的理解神经发育起源，这一目标在共识衍生的NINDS“2014年基准”中得到了强调，癫痫研究”的声明。