Ethanol and Reelin-dependent Plasticity During Fetal and Adolescent Periods

产前酒精暴露造成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。许多塑造早期发育的大脑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会再次发生。本提案将研究酒精（EtOH）暴露对调节发育中的产前和青春期大脑可塑性的信号通路的影响。Reelin-Dabi信号在产前发育期间控制皮层和海马的层压和树突发生，并在出生后分别增强记忆编码突触的长期增强（LTP）。Reelin- Dabi信号缺乏会导致人类大脑畸形、智力迟钝和癫痫。我们发现EtOH暴露，即使是急性剂量暴露，也会导致成熟神经元中Dabi蛋白水平的显著降低。大比是一种适应蛋白，是Reelin受体复合物的一个组成部分，是Reelin信号转导所绝对需要的。EtOH暴露会使Dabi水平降至正常值的-20%，这种水平会在发育过程中导致严重的大脑畸形，并可能在青春期导致功能变化。本研究将1)研究EtOH暴露后触发大比抑制的分子机制，然后确定EtOH诱导的大比抑制对2)产前树突生长和3)出生后海马可塑性或长期增强的影响。对EtOH和Reelin-Dabi之间的相互作用的研究，将为在胚胎和青少年大脑发育的关键阶段，EtOH对神经元可塑性产生负面影响的关键生化事件提供新的见解。

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.