Effects of Ethanol on Hippocampal Synaptic Plasticity

在神经发育过程中，酒精暴露会对大脑功能产生长期的不良影响，导致记忆缺陷和重大精神疾病的高风险。神经精神功能变化的潜在机制尚不清楚，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中枢神经系统（CNS）发育影响的重要信息。这些研究人员发现，在4小时的时间内，用中毒剂量的乙醇治疗早期产后大鼠，会导致中枢神经系统的许多区域，包括海马，出现大量的凋亡性神经变性。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可能会影响长期记忆功能。在本研究中，我们将研究出生后早期乙醇暴露对突触功能和可塑性的影响，使用青春期和年轻成年大鼠的体外海马切片，这些大鼠在海马细胞凋亡增加的年龄暴露于乙醇中。本项目的具体目标是：1。目的：探讨出生后早期乙醇暴露对海马CA1区基底突触传递、N-甲基-d -天冬氨酸谷氨酸受体（NMDARs）介导的突触反应的影响，以及nmdar依赖性长期增强（LTP）和长期突触抑制（LTD）的诱导阈值。在这些研究中，我们将使用出生后35天（P35）和P180大鼠制备的切片。2. 在出生后发育早期暴露于乙醇的青春期大鼠（P35）和成年大鼠（P180）中，海马形态和可塑性的变化如何转化为海马依赖的学习和记忆形式的变化。这些研究将建立在初步数据的基础上，这些数据表明，早期乙醇暴露会导致CA1海马区诱导同突触LTD的能力发生显著变化。希望更好地了解产后早期乙醇暴露如何改变海马体功能，将为胎儿酒精暴露导致的个体疾病提供更有效的治疗。

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.