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

• 批准号: 8323875
• 负责人: TIMOTHY A BENKE
• 金额: $ 33.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323875
• 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; conditioned fear; cytochemistry; human FRAP1 protein; improved; in vivo; kainate; mouse model; novel; programs; protein expression; therapeutic target; translational study; treatment strategy

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）：我们力求最终了解 3 个基本问题：(1) 生命早期癫痫发作 (ELS) 是否会引发具有自闭症表型的智力障碍 (ID)？ (2) ELS 触发的哪些信号传导程序可能是该表型的基础？ （3）改善突触可塑性和体内表型异常的合理、长期的药物治疗是什么？ 我们的初步研究提供了电生理学、药理学和生化证据，表明 ELS 会诱导与其他遗传形式的 ID 和自闭症类似的慢性表型，例如伴有 FMRP 功能障碍的脆性 X 病 (FRAX) 和伴有 mTOR 功能障碍的结节性硬化症 (TSC)。 我们提出了三个具体目标，利用电生理学、生物化学、免疫细胞化学和行为研究。研究将使用成年大鼠，在出生后第 7 天 (P) 进行单次红藻氨酸诱导的 ELS。这些研究将进一步研究电生理学测量的 mGluR-LTD 改变的机制，并检验 ELS 导致与其他遗传形式的自闭症类似的表型的假设。将与年龄匹配的注射生理盐水的对照进行比较。 具体目标 1：确定 ELS 后观察到的增强 mGluR 依赖性 LTD 的潜在机制。这将检验以下假设：ELS 后 mGluR 依赖性 LTD 发生改变，类似于基因破坏的 FMRP 表达介导的改变，并且可以以类似的方式进行药理学修饰。 具体目标 2：表征 ELS 后与 S6 激酶 (SK1) 过度激活相关的信号通路。这将检验这样的假设：ELS 后信号通路发生改变的方式与 FMRP 表达破坏和 mTOR 过度活跃介导的方式类似，分别如 FRAX 和 TSC 中那样。 具体目标 3：进一步表征 ELS 后的行为和电图体内表型。这将检验以下假设：除了异常恐惧调节之外的行为模式是由 ELS 诱发的，与自闭症样表型一致。 通过确定 ELS 后增强的 LTD 的药理调节剂，我们将确定这种可塑性的改变是否与 FRAX 和 TSC 相关的关键特征相同。我们在此提出的研究反映了 FRAX 和 TSC 中先进的药物干预措施。我们的研究将揭示其他形式的智力障碍和自闭症是否可能具有相同的药理学敏感性，并确定其他潜在的治疗靶点。这些研究将提出新的假设，即 FMRP 功能障碍可以在 FRAX 之外的 ID 和/或自闭症中看到。这可能会影响所有导致智力障碍和/或自闭症的治疗策略。我们的研究结果将支持我们的假设，即癫痫发作作为一种外部环境因素，直接影响智力障碍和/或自闭症表型的发展。这些假设不能以直接的方式在患者身上进行检验。使用我们的新型 ELS 动物模型触发具有自闭症表型的 ID，可以更直接地解决这些难以捉摸的临床问题。