Molecular mechanisms linking early life seizures, autism and intellectual disabil

生命早期癫痫发作、自闭症和智力障碍之间的分子机制

基本信息

批准号：
8909216
负责人：
TIMOTHY A BENKE
金额：
$ 33.19万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8909216
关键词：
Address Adult Affect Age Animal Model Autistic Disorder Behavioral Biochemical Biochemical Pathway Biological Assay Chronic Clinical Cognitive DLG4 gene Data Development Electroencephalography Environmental Risk Factor Enzymes Fragile X Mental Retardation Protein Fragile X Syndrome Functional disorder Genetic Hippocampus (Brain)Human Intellectual functioning disability Intervention Life Link Long-Term Depression MAPK3 gene Measures Mediating Mediator of activation protein Metabotropic Glutamate Receptors Modality Molecular Muscarinic Acetylcholine Receptor Newborn Infant Other Genetics Outcome Pathway interactions Patients Pharmacological Treatment Phenotype Protein phosphatase Proteins Proto-Oncogene Proteins c-akt Rattus Reading Ribosomal Protein S6 Kinase Rodent Model Saline Seizures Sensory Process Signal Pathway Signal Transduction Socialization Synapses Synaptic plasticity Testing Translations Tuberous Sclerosis behavioral study conditioned fear cytochemistry human FRAP1 protein improved in vivo kainate mouse model novel programs protein expression therapeutic target translational study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): We seek to ultimately understand 3 basic questions: (1) Do early-life seizures (ELS) trigger intellectual disability (ID) with an autistic phenotype? (2) What signaling programs triggered by ELS potentially underlie this phenotype? (3) What are the rational, long-term pharmacological treatments to improve the abnormalities in synaptic plasticity and the in vivo phenotype? Our preliminary studies provide electrophysiological, pharmacological and biochemical evidence to suggest that ELS induces a chronic phenotype similar to other genetic forms of ID and autism such as Fragile X (FRAX) with FMRP dysfunction and Tuberous Sclerosis (TSC) with mTOR dysfunction. We propose three specific aims, utilizing electrophysiological, biochemical, immuno-cytochemistry and behavioral studies. Studies will use adult rats following a single kainate-induced ELS at post-natal day (P) 7. These studies will further investigate the mechanisms underlying altered mGluR-LTD measured electrophysiologically and test the hypothesis that ELS leads to a phenotype similar to other genetic forms of autism. Comparisons will be made to age-matched saline injected controls. Specific Aim 1: Determine the mechanisms underlying enhanced mGluR-dependent LTD observed following ELS. This will test the hypothesis that mGluR-dependent LTD is altered following ELS similar to that mediated by genetically disrupted FMRP expression and can be modified pharmacologically in a similar fashion. Specific Aim 2: Characterize the signaling pathways associated with S6 kinase (SK1) hyperactivation following ELS. This will test the hypothesis that signaling pathways are altered following ELS in a similar fashion to that mediated by disrupted FMRP expression and hyperactive mTOR, as in FRAX and TSC, respectively. Specific Aim 3: Further characterize the behavioral and electrographic in vivo phenotype following ELS. This will test the hypothesis that behavioral modalities beyond abnormal fear conditioning are induced by ELS that are consistent with an autism-like phenotype. By determining the pharmacological modulators of enhanced LTD following ELS, we will determine if this alteration in plasticity shares key features with that associated with FRAX and TSC. The pharmacological interventions advanced in FRAX and TSC are mirrored by our studies proposed here. Our studies will inform whether other forms of ID and autism potentially may share their pharmacological sensitivity and determine other potential therapeutic targets. These studies will advance the novel hypothesis that FMRP dysfunction can be seen in ID and/or autism outside of FRAX. This could impact treatment strategies for all causes of ID and/or autism. Our findings will support our hypothesis that seizures, as an external environmental factor, directly influence the development of ID and/or an autistic phenotype. These hypotheses cannot be tested in a straightforward fashion in patients. The use of our novel animal model of ELS triggering ID with an autistic phenotype allows these elusive clinical questions to be addressed more directly.

描述（由申请人提供）：我们试图最终理解3个基本问题：（1）早期癫痫发作（ELS）是否会以自闭症表型触发智力障碍（ID）？（2）EL触发的哪些信号程序可能是该表型的基础？（3）哪些合理的长期药理治疗方法是改善突触可塑性异常和体内表型的异常？我们的初步研究提供了电生理，药理和生化证据，以表明ELS诱导与其他MTOR功能障碍的ID和自闭症其他遗传形式和自闭症的慢性表型相似。我们提出了三个特定的目标，利用电生理学，生化，免疫 - 周期化学和行为研究。研究将在产后日（P）7的单一海藻酸盐诱导的EL之后使用成年大鼠。这些研究将进一步研究MGLUR-LTD改变的机制，这些机制在电生理学上测量了MGLUR-LTD，并检验了ELS导致类似于其他遗传形式的表型的假设。将与年龄匹配的盐水注入的对照进行比较。特定目标1：确定在ELS之后观察到的增强的MGlur依赖性LTD的机制。这将检验以下假设：MGLUR依赖性LTD在ELS之后改变了类似于遗传破坏的FMRP表达介导的EL，并且可以以类似的方式进行药理修饰。特定目标2：表征与EL后与S6激酶（SK1）过度激活相关的信号通路。这将检验以下假设：在ELS以类似的方式介导的FMRP表达和分别与FRAX和TSC中的过度活跃MTOR介导的时，信号传导途径的变化是类似的。特定目标3：进一步表征EL后体内表型的行为和电图。这将检验以下假设：与自闭症样表型一致的EL引起了异常恐惧调节以外的行为方式。通过确定EL后增强LTD的药理学调节剂，我们将确定可塑性的这种变化是否与FRAX和TSC相关的变化具有关键特征。我们在这里提出的研究反映了FRAX和TSC中提出的药理干预措施。我们的研究将告知其他形式的ID和自闭症是否可能具有其药理敏感性并确定其他潜在的治疗靶标。这些研究将推进一个新的假设，即FMRP功能障碍可以在FRAX以外的ID和/或自闭症中看到。这可能会影响ID和/或自闭症的所有原因的治疗策略。我们的发现将支持我们的假设，即癫痫发作是外部环境因素，直接影响ID和/或自闭症表型的发展。这些假设不能以患者的直接方式进行检验。使用自闭症表型触发ID的新型动物模型的使用可以更直接地解决这些难以捉摸的临床问题。