Ethanol and Reelin-dependent Plasticity During Fetal and Adolescent Periods

产前酒精暴露引起的认知缺陷反映在酒精暴露儿童大脑中发现的特定功能和结构异常中。许多塑造早期大脑发育的分子和细胞事件在生命后期的可塑性或变化的关键时期再次发生。该提案将研究酒精（EtOH）暴露对调节发育中的产前和青少年大脑可塑性的信号通路的影响。Reelin-Dabi信号在出生前发育期间控制皮层和海马中的分层和树突发生，并且在出生后时期分别增强记忆编码突触的长时程增强（LTP）。Reelin- Dabi信号传导的缺陷会导致人类大脑畸形、智力迟钝和癫痫。我们发现，乙醇暴露，即使是急性剂量暴露，导致Dabi蛋白水平在成熟的神经元显着减少。Dabi是一种衔接蛋白，是Reelin受体复合物的组成部分，是Reelin信号传导所必需的。EtOH暴露可以使Dabi水平达到其正常值的约20%，已知该水平在发育期间会导致严重的脑畸形，并可能在青春期引起功能变化。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）产前期间树突生长和3）产后期间海马中的可塑性或长时程增强的后果。EtOH和Reelin-Dabi之间的这种相互作用的检查应该提供新的见解关键的生化事件，在胚胎和青少年大脑发育的关键阶段EtOH的神经元可塑性的负面影响的基础。

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.