Ethanol and Reelin-dependent Plasticity During Fetal and Adolescent Periods

胎儿和青少年时期乙醇和 Reelin 依赖性可塑性

基本信息

批准号：
9323204
负责人：
ERIC Christopher OLSON
金额：
$ 25.47万
依托单位：
STATE UNIVERSITY OF NY,BINGHAMTON
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/9323204
关键词：
Acute Adaptor Signaling Protein Adolescence Adolescent Affect Aging Alcohols Alleles Amplifiers Animals Axon Biochemical Biochemical Process Brain Cell Adhesion Molecules Child Cognitive deficits Complex Cortical Malformation Dendrites Development Disease Dose Embryo Epilepsy Ethanol Event Excitatory Postsynaptic Potentials Filopodia Fingers Future Genes Growth Heterozygote Hippocampus (Brain)Histologic Human In Vitro Learning Life Ligands Link Long-Term Potentiation Measures Memory Mental Retardation Molecular Molecular Target Mutant Strains Mice N-Methyl-D-Aspartate Receptors Nervous system structure Neuronal Plasticity Neurons Neurophysiology - biologic function Normal Range Pathway interactions Pharmacology Phenotype Preparation Property Proteins Protocols documentation Quantitative Reverse Transcriptase PCR Reaction Time Recovery Reelin Signaling Pathway Role Shapes Signal Pathway Signal Transduction Site Slice Structural defect Structure Synapses Synaptic Transmission Synaptic plasticity System Therapeutic adolescent brain development alcohol exposure alcohol research alcohol use disorder base brain malformation cell type combat critical period extracellular fetal in vivo insight memory encoding multiphoton imaging postnatal prenatal prenatal exposure prevent receptor function reelin receptor response synaptic function

项目摘要

The cognitive deficits caused by prenatal exposure to alcohol are reflected in the specific functional and structural abnormalities found in brains of alcohol-exposed children. Many of the same molecular and cellular events that shape the early developing brain reoccur later in life during critical periods of plasticity or change. This proposal will examine the impact of alcohol (EtOH) exposure on a signaling pathway that regulates plasticity in both the developing prenatal and adolescent brain. Reelin-Dabi signaling controls lamination and dendritogenesis in the cortex and hippocampus during prenatal development, and separately enhances long-term potentiation (LTP) of memory encoding synapses in the postnatal period. Deficiency in Reelin- Dabi signaling causes brain malformations, mental retardation and epilepsy in humans. We find that EtOH exposure, even acute dose exposure, causes a significant reduction of Dabi protein levels in maturing neurons. Dabi is an adaptor protein that is a component of the Reelin receptor complex and is absolutely required for Reelin signaling. EtOH exposure can drive Dabi levels to -20% of their normal value, levels that are known to cause serious brain malformations during development and likely functional changes in adolescence. This proposal will 1) examine the molecular mechanisms that trigger Dabi suppression after EtOH exposure and then determine the consequences of EtOH-induced Dabi suppression on 2) dendritic growth during the prenatal period and 3) plasticity or long term potentiation in the hippocampus during the postnatal period. The examination of this interaction between EtOH and Reelin-Dabi should provide new insight into key biochemical events that underlie EtOH's negative impacts on neuronal plasticity during the critical stages of embryonic and adolescent brain development.

产前接触酒精引起的认知缺陷反映在接触酒精的儿童大脑中发现的特定功能和结构异常。许多塑造早期发育大脑的相同分子和细胞事件在生命后期的可塑性或变化的关键时期会再次发生。该提案将研究酒精 (EtOH) 暴露对调节产前和青少年大脑发育可塑性的信号通路的影响。 Reelin-Dabi 信号控制产前发育期间皮层和海马的分层和树突发生，并分别增强产后记忆编码突触的长期增强 (LTP)。 Reelin-Dabi 信号传导缺陷会导致人类大脑畸形、智力低下和癫痫。我们发现，乙醇暴露，即使是急性剂量暴露，也会导致成熟神经元中 Dabi 蛋白水平显着降低。 Dabi 是一种接头蛋白，是 Reelin 受体复合物的组成部分，并且是 Reelin 信号传导所必需的。接触 EtOH 会使 Dabi 水平降至正常值的 -20%，已知该水平会导致发育过程中严重的大脑畸形，并可能导致青春期的功能变化。该提案将 1) 检查 EtOH 暴露后触发 Dabi 抑制的分子机制，然后确定 EtOH 诱导的 Dabi 抑制对 2) 产前树突生长和 3) 产后海马可塑性或长期增强的影响时期。对 EtOH 和 Reelin-Dabi 之间这种相互作用的检查应该为关键生化事件提供新的见解，这些生化事件是 EtOH 在胚胎和青少年大脑发育关键阶段对神经元可塑性产生负面影响的基础。