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
基本信息
- 批准号:10304051
- 负责人:
- 金额:$ 3.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AgonistAnatomyAnimalsApplications GrantsAreaAwardBrainBrain InjuriesBrain-Derived Neurotrophic FactorCell DeathCellsChronicComplementDataDevelopmentElectrophysiology (science)EpilepsyEpileptogenesisFailureFrequenciesGoalsGrantIn VitroIncidenceInhibitory SynapseInjuryInterneuron functionInterneuronsLightLong-Term EffectsMaintenanceMeasuresModelingMorphologyMusNeocortexNerveNeuronsNeurotrophic Tyrosine Kinase Receptor Type 2OutputParvalbuminsPharmacologyPhysiologicalPhysiologyPresynaptic TerminalsProbabilityPropertyProphylactic treatmentReportingResearchResearch TrainingSalineSeizuresSliceSomatostatinStatus EpilepticusStructural defectStructureSynapsesSynaptic TransmissionTechniquesTestingTrainingTraumaTropomyosinUnited States National Institutes of Healthbasebrain abnormalitiescareerconfocal imagingdensityexperienceexperimental studygamma-Aminobutyric Acidgephyrinhippocampal pyramidal neuronimmunocytochemistryimproved functioninginhibitory neuronmouse modelneocorticalnervous system disorderneuronal cell bodynovel strategiesparent grantpostsynapticpreventpreventable epilepsyreceptorsmall moleculesynaptogenesistransmission process
项目摘要
Project Summary
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 activation of TrkB receptors (TrkB-Rs). 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. The parent grant main goal is to determine whether these effects will be applicable to
treatment or prevention of epilepsy in other models with different causes for seizures. The objective is to
determine whether chronic treatment with a TrkB-Rs partial agonist, by increasing GABA release from nerve
terminals of interneurons, or inducing new inhibitory synapse formation, will enhance inhibition in cortical
networks and suppress epileptiform discharges. The specific aims of the parent grant include to: i) test the
hypothesis that activation of TrkB-Rs with LM will reverse or prevent structural abnormalities in FS
interneurons of UC cortex; ii) Examine effects of TrkB-Rs activation on functional properties of GABAergic
inhibition in layer V; iii) Test the effects of LM on cortical network activity in UC animals. Proposed experiments
include a) immunocytochemistry and confocal imaging to assess alterations in presynaptic terminals of
interneurons; b) 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. For this supplement grant we will study the effects of focal status
epilepticus (FSE) on numbers, morphology and physiology of GABAergic interneurons in the cortical network
and test possible mitigating effects of activation of TrkB-Rs with a small molecule partial agonist, PTXBD4-3
(BD). These results will complement and extend Aims 1, and 2 of the parent grant. 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. Considering the frequency and untoward consequences of FSE, results may have
potential translational importance.
项目摘要
据报道,在许多神经元中,小清蛋白(PV)和生长抑素(SOM)中间神经元的表达减少。
神经系统疾病,包括癫痫。改善有缺陷的中间神经元功能的疗法不是
available.中间神经元的结构发育和维持依赖于提供的营养支持
通过脑源性神经营养因子激活TrkB受体(TrkB-Rs)。在底切(UC)模型中,
致痫性新皮层损伤,选择性小分子部分激动剂慢性激活TrkB-Rs
(LM 22 A-4,下文“LM”)具有逆转抑制性细胞凋亡中的结构和功能异常的长期作用。
PV中间神经元终末,增强GABA释放,提高诱发癫痫样放电的阈值
活动和癫痫。父母补助金的主要目标是确定这些影响是否适用于
治疗或预防其他模型中具有不同癫痫发作原因的癫痫。目标是
确定是否用TrkB-Rs部分激动剂进行慢性治疗,通过增加从神经释放的GABA
终末或诱导新的抑制性突触的形成,都将增强皮层的抑制作用。
网络和抑制癫痫样放电。父母补助金的具体目标包括:
假设LM中TrkB-R的激活将逆转或防止FS中的结构异常
ii)检查TrkB-Rs活化对UC皮质的GABA能神经元的功能性质的影响;
iii)测试LM对UC动物中皮质网络活性的影响。拟议实验
包括a)免疫细胞化学和共聚焦成像,以评估
B)来自PV的抑制性突触传递的基本性质的电生理学分析
中间神经元到锥体神经元的体外切片以检测TrkB活化对单一IPSC的影响,
释放概率和传输故障。对于这项补助金,我们将研究焦点地位的影响,
癫痫发作(FSE)对皮层网络中GABA能中间神经元数量、形态和生理的影响
并测试用小分子部分激动剂PTXBD 4 -3激活TrkB-R的可能缓解作用
(BD)中所示。这些结果将补充和扩展母赠款的目标1和2。结果进行
实验将提供有关导致神经元间异常的机制的信息,
癫痫的发生和通过增强营养预防癫痫发生的潜在途径
支持interneurons。考虑到FSE的频率和不良后果,结果可能会
潜在的翻译重要性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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David Allan Prince其他文献
David Allan Prince的其他文献
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{{ truncateString('David Allan Prince', 18)}}的其他基金
Effects of pregabalin and thrombospondins on enhanced excitatory connectivity, new synapse formation and epileptogenesis after neocortical injury
普瑞巴林和血小板反应蛋白对新皮质损伤后兴奋性连接增强、新突触形成和癫痫发生的影响
- 批准号:
9308032 - 财政年份:2014
- 资助金额:
$ 3.83万 - 项目类别:
Effects of pregabalin and thrombospondins on enhanced excitatory connectivity, new synapse formation and epileptogenesis after neocortical injury
普瑞巴林和血小板反应蛋白对新皮质损伤后兴奋性连接增强、新突触形成和癫痫发生的影响
- 批准号:
8802778 - 财政年份:2014
- 资助金额:
$ 3.83万 - 项目类别:
Effects of TrkB Activation on Abnormalities in Neocortical FS Interneurons
TrkB 激活对新皮质 FS 中间神经元异常的影响
- 批准号:
9021010 - 财政年份:2013
- 资助金额:
$ 3.83万 - 项目类别:
Effects of TrkB Activation on Abnormalities in Neocortical FS Interneurons
TrkB 激活对新皮质 FS 中间神经元异常的影响
- 批准号:
8623158 - 财政年份:2013
- 资助金额:
$ 3.83万 - 项目类别:
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:
9912860 - 财政年份:2013
- 资助金额:
$ 3.83万 - 项目类别:
Effects of TrkB Activation on Abnormalities in Neocortical FS Interneurons
TrkB 激活对新皮质 FS 中间神经元异常的影响
- 批准号:
9231510 - 财政年份:2013
- 资助金额:
$ 3.83万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 3.83万 - 项目类别:
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:
10598731 - 财政年份:2013
- 资助金额:
$ 3.83万 - 项目类别:
Effects of TrkB Activation on Abnormalities in Neocortical FS Interneurons
TrkB 激活对新皮质 FS 中间神经元异常的影响
- 批准号:
8484109 - 财政年份:2013
- 资助金额:
$ 3.83万 - 项目类别:
NEURONAL EXCITABILITY IN CHRONIC EPILEPTOGENESIS
慢性癫痫发生中的神经元兴奋性
- 批准号:
6989025 - 财政年份:2004
- 资助金额:
$ 3.83万 - 项目类别:
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