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）： 癫痫发作是由于大脑中神经元异常、超同步放电导致的突然发作或抽搐。大约 5-10% 的人一生中会经历一次癫痫发作。高热惊厥是婴儿晚期和儿童早期癫痫发作的最常见原因。尽管这种类型的癫痫发作在世界各地都很普遍，但人们对其机制知之甚少。最近的一项研究表明，发烧会导致换气过度和呼吸性碱中毒，而大脑 pH 值升高可能是热性惊厥的直接原因。在我提出的项目中，我计划检验以下假设：温度和 pH 值引起的抑制回路变化会导致热性惊厥的发生。首先，我将研究海马 CA1 场自发和诱发的细胞外场电位在高温和高 pH 条件下如何变化。这些结果将使我能够确定高温、高 pH 值或两者的组合是否会增加过度兴奋性。其次，我将使用全细胞贴片记录方法来评估温度或 pH 值变化是否会改变两种特定类型的抑制性中间神经元或锥体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锥体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细胞的亚阈值和活性特性。我将测量自发突触活动以及特定的兴奋性和抑制性突触连接的变化。我将把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癫痫样活动的发生联系起来。第三，我将通过比较 TRPV1 敲除小鼠与野生型小鼠，研究温度和 pH 敏感瞬时受体潜在缬氨酸受体 1（TRPV1 受体）激活在高温和/或 pH 条件下增加神经元兴奋性的潜在作用。将使用体内和体外方法来全面评估TRPV1受体的潜在作用。 我的结果应该对我们理解发热的基本机制有重大贡献 癫痫发作。通过更好地了解热性惊厥的原因，我们也许能够优化预防和治疗。这项工作将直接有助于 NINDS 减轻神经系统疾病负担的使命。