Ethanol and Reelin-dependent Plasticity During Fetal and Adolescent Periods

出生前接触酒精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上。塑造早期大脑发育的许多相同的分子和细胞事件，在生命后期的可塑性或变化的关键时期重复发生。这项建议将研究酒精(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信号在出生前控制大脑皮质和海马区的分层和树突发生，并在出生后分别增强记忆编码突触的长时程增强(LTP)。Reelin-Dabi信号的缺陷会导致人类的大脑畸形、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蛋白水平的显著降低。Dabi是一种连接蛋白，是Reelin受体复合体的组成部分，是Reelin信号传递所必需的。接触乙醇可使DABI水平降至正常值的-20%，这一水平已知会在发育期间导致严重的大脑畸形，并可能在青春期导致功能变化。这项建议将1)研究乙醇暴露后触发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)出生后海马区可塑性或长期增强的后果。对Etoh和Reelin-Dabi之间这种相互作用的研究应该会为Etoh在胚胎和青春期大脑发育的关键阶段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.