AMPA receptor dynamics and recruitment of seizure activity in a model of cortal

AMPA 受体动力学和皮质模型中癫痫活动的募集

基本信息

批准号：
7876752
负责人：
John R Huguenard
金额：
$ 28.84万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7876752
关键词：
AMPA Receptors Antiepileptic Agents Area Brain Brain-Derived Neurotrophic Factor Cell Nucleus Cells Cortical Dysplasia Data Dendrites Development Epilepsy Event Excitatory Synapse Fiber Freezing Generations GluR2 subunit AMPA receptor Glutamate Receptor Glutamates Goals In Vitro Injury Lasers Lead Lesion Location Maps Measures Mediating Membrane Microgyria Modeling Molecular N-Methyl-D-Aspartate Receptors Neocortex Neurons Output Pentobarbital Phenotype Physiologic pulse Physiological Polyamines Property Protein Kinase C Pyramidal Cells Rattus Receptor Activation Recruitment Activity Recurrence Regulation Relative (related person)Research Research Personnel Role Scanning Seizures Site Slice Spermine Synapses Synaptic Receptors Synaptic plasticity Testing density drug development hippocampal pyramidal neuron indexing inhibitory neuron injured malformation neocortical neural circuit neuronal cell body neuronal excitability novel patch clamp photolysis postsynaptic presynaptic prevent programs receptor receptor expression receptor function research study response therapeutic target therapy development tool

项目摘要

Epilepsy results from abnormal recruitment of recurrent excitatory synaptic circuits in the neocortex. The long term goals of this project are to determine the mechanisms underlying epileptic recruitment and to develop therapies that will prevent it. In the developing brain excitatory neocortical networks are synaptically connected via an immature form of postsynaptic ionotropic glutamate receptor that lack the GluR2 receptor subunit. Synapses lacking this subunit show dynamic forms of synaptic plasticity not normally seen in mature neurons, which prominently express synaptic GluR2 receptors. Our preliminary data suggests that in the cortical freeze lesion (microgyrus) model of focal cortical dysplasia, neocortical pyramidal neurons express immature forms of synaptic glutamate receptors and display prominent epileptiform hyperexcitability that is recruited by focal molecular uncaging of glutamate. In the first aim of the proposed experiments we will use in vitro electrophysiological means to determine the mechanisms underlying BDNF- and PKC- mediated plasticity of synaptic receptors in immature neocortical circuits. In addition we will test whether such plasticity exists in synapses of the microgyrus model. In the second aim we will utilize laser scanning photostimulation to determine the mechanisms underlying the abnormal recruitment of epileptiform electrical responses in the microgyrus model. The results of these studies will provide information relevant to our understanding of the mechanisms underlying focal cortical seizures, and may indicate therapeutic targets for antiepileptic drug development.

癫痫病来自新皮层中复发性兴奋性突触回路的异常募集。这该项目的长期目标是确定癫痫招募的基础机制和开发疗法可以阻止它。在发育中的大脑兴奋性新皮质网络中通过缺乏GlUR2受体的突触后离子谷氨酸受体的未成熟形式连接亚基。缺乏该亚基的突触显示了通常在成熟的神经元，显着表达突触Glur2受体。我们的初步数据表明局灶性皮质发育不良，新皮层锥体神经元的皮质冻结病变（微胶质）模型突触的突触谷氨酸受体的未成熟形式，并显示出明显的癫痫表现过度抗性性这是通过谷氨酸局灶性分子未塞募集的。在提出的实验的第一个目的中将使用体外电生理手段来确定BDNF-和PKC-的机制未成熟的新皮质电路中突触受体的介导的可塑性。此外，我们将测试是否这种可塑性存在于Microgyrus模型的突触中。在第二个目标中，我们将使用激光扫描光刺激以确定癫痫表募集异常募集的机制 Microgyrus模型中的响应。这些研究的结果将提供与我们相关的信息了解局灶性皮质癫痫发作的机制，并可能表明治疗靶点抗癫痫药开发。