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.

在酒精暴露的儿童的大脑中发现的特定功能和结构异常反映了产前暴露于酒精引起的认知缺陷。许多相同的分子事件和细胞事件，这些事件塑造了早期生命早期在关键时期或变化期间生命后期重生的情况。该提案将检查酒精（ETOH）暴露对调节发育中和青少年大脑中可塑性的信号通路的影响。 reelin-dabi信号传导控制产后发育过程中皮质和海马中的层压和树突发生，并在产后时期分别增强了编码突触的记忆的长期增强（LTP）。 relindabi信号的缺乏会导致人类的脑畸形，智力低下和癫痫病。我们发现ETOH暴露，甚至急性剂量暴露，都会显着降低成熟神经元中的DABI蛋白水平。 DABI是一种衔接蛋白，是reelin受体复合物的组成部分，绝对是reelin信号传导所必需的。 EtOH暴露会使DABI水平达到其正常值的-20％，这些水平已知在发育过程中会导致严重的脑畸形以及青春期可能的功能变化。该提案将1）检查触发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）在产前期间的树突状生长和3）海马期间在海马期间的可变或长期增强的后果。对ETOH和Reelin-Dabi之间这种相互作用的研究应提供对关键生物化学事件的新见解，这些事件是ETOH对胚胎和青少年脑发育的关键阶段中对神经元可塑性的负面影响。