Ethanol-Neurosteroid Actions on Synaptic Transmission

描述(申请人提供)：慢性酒精会导致许多神经障碍，包括记忆和认知障碍。海马区突触传递的改变可能是乙醇对学习和记忆影响的基础。有研究表明，乙醇对中枢神经系统功能的影响可能是由脑内从头合成的神经类固醇所介导的。乙醇和神经类固醇通过与N-甲基-D-天冬氨酸(NMDA)和γ-氨基丁酸受体相互作用，影响兴奋性和抑制性突触传递。然而，目前尚不清楚慢性乙醇如何改变神经类固醇对海马区突触功能的调制效应，而海马区突触功能对记忆处理至关重要。该提案将侧重于孕烯醇酮硫酸盐(PREGS)，一种有效的记忆增强神经类固醇，以及它与乙醇在NMDA受体介导的突触传递和增强中的相互作用。正在测试的假设是，慢性间歇性乙醇(CIE)治疗改变了NMDA受体介导的对孕激素的突触反应。将测量乙醇-NaI和CIE处理的大鼠海马片中CA1神经元的场兴奋性突触后电位。CIE治疗对前列环素诱导的NMDA受体介导的突触传递和长时程增强的影响将被研究。此外，这些改变的持久性将在退出CIE治疗的大鼠的神经元切片中进行检查。最后，将确定在乙醇和孕激素对长时程增强的相互作用中是否涉及激酶活性的变化。总而言之，这些实验将促进我们对神经类固醇调节突触功能的变化的理解，这些变化可能对乙醇的中枢神经系统活动至关重要。

DESCRIPTION (provided by applicant): Chronic ethanol produces many neurological disorders, including memory and cognitive impairments. Alterations in hippocampal synaptic transmission may underlie the effects of ethanol on learning and memory. It has been suggested that the effects of ethanol on CNS function may be mediated by neurosteroids, which are synthesized de novo in brain. Both ethanol and neurosteroids influence excitatory and inhibitorysynaptic transmission by interacting with N-methyl-d-aspartate (NMDA)- and gamma-aminobutyric acid receptors. However, it is not clear how chronic ethanol alters the modulatory effects of neurosteroids on hippocampal synaptic function that is important for memory processing. The proposal will focus on pregnenolone sulfate (PREGS), a potent memory-enhancing neurosteroid, and its interaction with ethanol on NMDA receptor-mediated synaptic transmission and potentiation. The hypothesis being tested is that NMDA receptor-mediated synaptic responses to PREGS are altered by chronic intermittent ethanol (CIE) treatment. Field excitatory post synaptic potentials will be measured from CA1 neurons in hippocampal slices prepared from ethanol-nai've and CIE treated rats. The effect of CIE treatment on PREGSinduced changes in NMDA-receptor mediated synaptic transmission and long-term potentiation will be investigated. Furthermore, the persistence of these alterations will be examined in neuronal slices from rats withdrawn from CIE treatment. Finally, it will be determined whether alterations in kinase activity are involved in the interactions of ethanol and PREGS on long-term potentiation. Collectively, the experiments will advance our understanding of changes in neurosteroid modulation of synaptic function that may be important to the CNS actions of ethanol.