Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron

TrkB 激活对新皮质 FS 中间神经元异常的影响

• 批准号: 10393566
• 负责人: David Allan Prince
• 金额: $ 34.44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393566
• 关键词: Action Potentials; Affect; Agonist; Axon; Brain; Brain-Derived Neurotrophic Factor; Calcium; Cells; Chronic; Confocal Microscopy; D Cells; Data; Dendrites; Development; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Etiology; Failure; Frequencies; Functional disorder; Genes; Genetic; High temperature of physical object; Hot Spot; Impairment; Implant; In Vitro; Incidence; Induced Hyperthermia; Inhibitory Synapse; Injury; Interneuron function; Interneurons; Label; Lasers; Length; Long-Term Effects; Maintenance; Maps; Measures; Membrane; Modeling; Monitor; Mus; Myoepithelial cell; Neocortex; Nerve; Neurons; Neuropil; Neurotrophic Tyrosine Kinase Receptor Type 2; Parvalbumins; Pharmaceutical Preparations; Predisposition; Presynaptic Terminals; Probability; Property; Prophylactic treatment; Proteins; Pyramidal Cells; Reporting; Research; Saline; Scanning; Seizures; Severities; Slice; Sodium Channel; Somatostatin; Structure; Synapses; Synaptic Transmission; Temperature; Testing; antagonist; axonal sprouting; biocytin; brain dysfunction; childhood epilepsy; comorbidity; confocal imaging; de novo mutation; density; dravet syndrome; experimental study; gamma-Aminobutyric Acid; gephyrin; hippocampal pyramidal neuron; immunocytochemistry; improved functioning; in vivo; inhibitory neuron; mouse model; neocortical; nerve supply; nervous system disorder; neuronal cell body; novel strategies; postsynaptic; presynaptic; preventable epilepsy; sensor; small molecule; synaptogenesis; synaptotagmin II; transmission process; treatment effect

Abnormalities in parvalbumin (PV) and somatostatin (SOM) interneurons are reported in a number of neurological disorders, including epilepsy. Therapy that improves function of defective interneurons is not available. Structural development and maintenance of interneurons is dependent on trophic support provided by brain derived neurotrophic factor (BDNF) activation of TrkB receptors. In the undercut (UC) model of epileptogenic neocortical injury, chronic activation of TrkB-Rs with a selective small molecule partial agonist (LM22A-4, “LM” below) has long-term effects to reverse structural and functional abnormalities in inhibitory terminals of PV interneurons, enhance GABA release and increase the threshold for evoking epileptiform activity and seizures. In order to determine whether these effects will be applicable to treatment or prevention of epilepsy in other models with different causes for seizures, such as genetic epilepsies, the Dravet syndrome (DS) mouse will be used in some experiments. Decreases in a membrane sodium channel in PV interneurons in DS mice causes decreased release of the inhibitory transmitter GABA, and development of spontaneous and high temperature-induced seizures. A variety of experimental approaches in DS and UC mice will be used to determine whether chronic treatment with LM, by increasing GABA release from nerve terminals of SOM and PV interneurons, or inducing new inhibitory synapse formation, will enhance inhibition in cortical networks and suppress epileptiform discharges: 1) immunocytochemistry and confocal imaging will be used to assess alterations in PV and SOM presynaptic terminals, including changes in expression of VGAT- and GAD65/67- IR, and the calcium sensor protein synaptotagmin 2; 2) analysis of density of SOM/- and PV/gephyrin close appositions to test for new inhibitory synapse formation induced by TrkB activation; 3) electrophysiological analysis of basic properties of inhibitory synaptic transmission from PV interneurons to pyramidal neurons of in vitro slices to detect effects of TrkB activation on unitary IPSCs, release probability and transmission failures; 3) laser scanning photostimulation of cortical slices from PV/CHR2 and SOM/CHR2 mice to map the distribution and strength of inhibitory connectivity in neocortical inhibitory circuits; and 4) video/EEG monitoring of implanted mice to assess effects of treatment with LM on spontaneous seizures and hyperthermia-induced seizures. Results of these experiments will provide information about mechanisms leading from interneuronal abnormalities to development of epilepsy and a potential approach to prophylaxis of epileptogenesis by enhancing trophic support of interneurons.

据报道，白蛋白（PV）和生长抑素（SOM）中间神经元异常 神经系统疾病，包括癫痫病的疗法。 可用。 通过脑衍生的神经营养因子（BDNF）激活TRKB受体。 癫痫病新皮质损伤，具有选择性的小分子部分激动剂的TRKB-RS慢性激活 （下面的LM22A-4，“ LM”）具有长期效果，可以逆转遗传的结构和功能异常 PV中间神经元的末端，增强GABA释放并增加唤起唤起唤起唤起癫痫发作的阈值 活动和癫痫发作。 在其他具有不同原因癫痫病因的模型中的癫痫病，例如遗传性癫痫，Dravet综合征 （DS）在某些实验中使用小鼠 在DS小鼠中，导致抑制性发射器GABA的释放减少，并自发发展 和高温引起的癫痫发作。 通过增加SOM神经末端的GABA释放来确定是否使用LM进行慢性治疗 和PV Interneulons，或诱导新的不合时宜的突触形成，将增强Inhibernetworks 并抑制癫痫样放电：1）免疫细胞化学和共聚焦成像将用于评估 PV和某些突触前末端的改变，VGAT和GAD65/67-的Express的包含变化 IR和钙传感器蛋白突触tap蛋白2； 2） 由TRKB激活指示的新nehibinity突触形成； 3）电生理学 分析抑制性突触从PV中间神经元到IN in in in in in in in in in in的基本特性。 体外缝隙可检测TRKB激活对单一IPSC的影响，释放概率和传输故障； 3）从PV/CHR2和SOM/CHR2小鼠绘制的皮质缝的激光扫描光刺激 新皮质侵入性电路（和4）视频/脑电图监测 小鼠评估LM治疗对自发性癫痫发作和高温治疗的影响 癫痫发作。 癫痫发育的异常以及一种潜在的预防癫痫发生的方法 增强对中间神经元的奖学金支持。