Role of inhibitory interneurons in generating febrile seizures

抑制性中间神经元在热性惊厥发生中的作用

• 批准号: 7486546
• 负责人: Jennifer A Kim
• 金额: $ 3.59万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486546
• 关键词: Action Potentials; Acute; Address; Adolescent; Adult; Animal Model; Brain; Cells; Characteristics; Condition; Convulsions; Development; Epilepsy; Evoked Potentials; Excitatory Synapse; Febrile Convulsions; Fever; Fire - disasters; Generations; Grant; High temperature of physical object; Hippocampus (Brain); Hyperventilation; In Vitro; Interneurons; Knock-out; Limbic System; Link; Localized; Location; Measures; Membrane; Methods; Mission; Modification; Neocortex; Neurons; Play; Population; Preparation; Property; Prophylactic treatment; Rate; Receptor Activation; Resistance; Respiratory Alkalosis; Role; Seizures; Site; Slice; Stimulus; Synapses; TRPV1 gene; Temperature; Temporal Lobe Epilepsy; Testing; Time; Whole-Cell Recordings; Wild Type Mouse; Work; afterpotential; early childhood; experience; extracellular; falls; hippocampal pyramidal neuron; in vivo; infancy; insight; nervous system disorder; neuronal excitability; postsynaptic; receptor; voltage

DESCRIPTION (provided by applicant): Seizures are sudden attacks or convulsions due to abnormal, hypersynchronous discharges from a population of neurons in the brain. Approximately 5-10% of people will experience one seizure in their lifetime. Febrile seizures are the most common cause of seizures in late infancy and early childhood. Though this type of seizure is prevalent throughout the world, very little is known about its mechanisms. A recent study suggested that fever induces hyperventilation and respiratory alkalosis, and that an increase in brain pH may be the proximate cause of febrile seizures. In my proposed project, I plan to test the hypothesis that temperature- and pH-induced changes of inhibitory circuits contribute to the generation of febrile seizures. First, I will examine how spontaneous and evoked extracellular field potentials in the CA1 field of the hippocampus change under conditions of high temperature and high pH. These results will allow me to determine whether high temperature, high pH or the combination of both increase hyperexcitability. Second, I will use whole-cell patch recording methods to evaluate whether temperature or pH changes alter the intrinsic membrane excitability and synaptic connections of two specific types of inhibitory interneurons or pyramidal neurons. I will use whole-cell recordings from pairs of identified interneurons or from interneuronpyramidal cell pairs. I will use small hyperpolarizing and depolarizing current steps to measure both subthreshold and active properties of each cell. I will measure changes in spontaneous synaptic activity and specific excitatory and inhibitory synaptic connections. I will correlate changes in synaptic and intrinsic properties of inhibitory interneurons with the onset of epileptiform activity in local networks. Third, I will investigate the potential role of temperature- and pH-sensitive transient receptor potential vallinoid receptor 1 (TRPV1 receptor) activation in increasing neuronal excitability during high temperature and/or pH conditions by comparing TRPV1 knockout to wild-type mice. Both in vivo and in vitro methods will be used to fully evaluate the potential effects of TRPV1 receptors. My results should contribute significantly to our understanding of the basic mechanisms of febrile seizures. With better insight into the causes of febrile seizures, we may be able to optimize prophylaxis and treatment. This work would contribute directly to the mission of NINDS to reduce the burden of neurological disease.

描述（由申请人提供）： 癫痫发作是由于异常，从大脑中的神经元种群中的超同步放出引起的突然攻击或抽搐。大约5-10％的人将在他们的一生中遭受一次癫痫发作。发热性癫痫发作是婴儿晚期和幼儿期间癫痫发作的最常见原因。尽管这种癫痫发作在世界范围内普遍存在，但对其机制知之甚少。最近的一项研究表明，发烧会诱导过度换气和呼吸碱中毒，并且脑pH的增加可能是发热性癫痫发作的直接原因。在我提出的项目中，我计划检验以下假设：温度和pH诱导的抑制回路变化有助于发热发作的产生。首先，我将检查在高温和高pH的条件下，海马变化的CA1场中的自发和诱发细胞外场电位如何。这些结果将使我能够确定高温，高pH值还是同时增加过度兴奋性。其次，我将使用全细胞斑块记录方法来评估温度或pH变化是否会改变两种特定类型的抑制性神经元或金字塔神经元的内在膜兴奋性和突触连接。我将使用来自已识别的中间神经元对或神经元间细胞对的全细胞记录。我将使用小的超极化和去极化电流步骤来测量每个单元的子阈值和活性特性。我将衡量自发突触活动以及特定兴奋性和抑制性突触连接的变化。我将将抑制性中间神经元的突触和内在特性的变化与局部网络中的癫痫样活性发作相关联。第三，我将研究温度和pH敏感的瞬态受体潜在的vallinoid受体1（TRPV1受体）激活在高温和/或pH条件下通过比较野生型小鼠在高温和/或pH条件下增加神经元兴奋性的潜在作用。体内和体外方法都将用于充分评估TRPV1受体的潜在影响。 我的结果应该对我们对高温基本机制的理解做出重大贡献 癫痫发作。有了更好地洞悉发热性癫痫发作的原因，我们可能能够优化预防和治疗。这项工作将直接有助于Ninds的使命，以减轻神经疾病的负担。