Effects of Ethanol on Hippocampal Synaptic Plasticity

在神经发育过程中接触酒精可能会对大脑功能产生长期的不利影响，导致记忆障碍，并有很高的患重大精神疾病的风险。神经精神功能变化背后的机制尚不清楚，但被认为是由于对突触传递的影响。最近，Olney和他的同事提供了关于乙醇对发育中的中枢神经系统(CNS)的影响的重要信息。这些研究人员发现，对出生后早期的大鼠进行四个小时的酒精中毒治疗，会导致包括海马体在内的中枢神经系统许多区域出现大规模的神经细胞凋亡性变性。由于海马体在记忆处理中起着关键作用，因此该结构的早期损伤很可能会影响长期记忆功能。在这项建议中，我们将使用青少年和年轻成年大鼠在酒精暴露的年龄与海马区细胞凋亡增加相关的青春期和年轻成年大鼠的体外海马片，研究出生后早期酒精暴露对突触功能和可塑性的影响。本课题的具体目的是：1.研究生后早期酒精暴露对大鼠海马脑片CA1区基础突触传递、N-甲基-D-天冬氨酸受体(NMDAR)介导的突触反应以及NMDAR依赖的长时程增强(LTP)和长时程增强(LTD)的影响。在这些研究中，我们将使用从出生后第35天(P35)和P180大鼠准备的切片。2.研究酒精对幼年(P35)和成年(P180)幼年和成年(P180)大鼠的影响。这些研究将建立在初步数据的基础上，这些数据表明，早期酒精暴露会导致CA1海马区诱导同源突触LTD的能力发生显著变化。人们希望，更好地了解出生后早期酒精暴露如何改变海马体功能，将有助于更有效地治疗因胎儿酒精暴露而导致疾病的个体。

Ethanol exposure during neurodevelopment can have long- term adverse effects on brain function, resulting in defects in memory and a high risk for major psychiatric disorders. The mechanisms underlying the changes in neuropsychiatric function are poorly understood but thought to result from effects on synaptic transmission. Recently, Olney and colleagues provided important information about the effects of ethanol on the developing central nervous system (CNS). These investigators found that treatment of early postnatal rats with intoxicating doses of ethanol over a single four hour period results in massive apoptotic neurodegeneration in many regions of the CNS, including the hippocampus. Because the hippocampus plays a key role in memory processing, it is likely that early damage to this structure influences longer-term memory function. In this proposal, we will examine the consequences of early postnatal ethanol exposure on synaptic function and plasticity using in vitro hippocampal slices prepared from adolescent and young adult rats exposed to ethanol at ages associated with augmented hippocampal apoptosis. The specific aims of this project are: 1. To determine the effects of early postnatal ethanol exposure on basal synaptic transmission, synaptic responses mediated by N- methyl-D-aspartate glutamate receptors (NMDARs) and the threshold for induction of NMDAR-dependent long-term potentiation (LTP) and long-term synaptic depression (LTD) in the CA1 region of hippocampal slices. For these studies we will use slices prepared from postnatal day 35 (P35) and P180 rats. 2. To determine how changes in hippocampal morphology and plasticity translate into changes in hippocampal-dependent forms of learning and memory in adolescent (P35) and adult (P180) rats exposed to ethanol early in postnatal development. These studies will build on preliminary data indicating that early ethanol exposure results in significant changes in the ability to induce homosynaptic LTD in the CA1 hippocampal region. It is hoped that better understanding of how early postnatal ethanol exposure alters hippocampal function will lead to more effective treatments for individuals with disorders resulting from fetal alcohol exposure.