Endocannabinoid Signaling in Postnatal Ethanol Effects

 描述(申请人提供)：胎儿酒精谱系障碍(FASD)是西方国家智力残疾的主要原因之一，其神经行为特征包括学习和记忆障碍。我们在当前资助期间的数据揭示了anandamide(AEA)和大麻素1型受体(CB1R)作为出生后乙醇暴露的新生小鼠(出生后第7天，P7)神经变性(ND)的调节因子的新功能，这与成年小鼠的突触功能障碍有关。在这个应用中，我们认为出生后酒精暴露会导致CB1R功能的持续增强，从而破坏突触的动态平衡和学习记忆。虽然长期暴露的范例可能更接近于FASD的常见病因，但狂欢模型允许更精确地分析机制，从而为治疗提供潜在的治疗靶点。我们用出生后乙醇模型的试点数据支持，在新生儿中观察到的CB1R活性增强一直持续到成年，而在出生后长期接触乙醇后阻断CB1R能够挽救成年人的空间记忆缺陷。这一更新应用的超常目标是更好地理解和定义导致CB1R持续表达的分子事件，以及它对成年小鼠观察到的突触电路发育、活动依赖信号、突触结构和神经行为异常的影响。目标1的目的是验证出生后酒精暴露诱导CB1R持续表达到成年的假设，并检查CB1R启动子上支持CB1R在新皮质和海马区结构中表达增强的组蛋白和DNA修饰。特定目标2将测试假设，出生后酒精诱导CB1R的持续表达扰乱突触电路的发育和可能参与突触活动的神经元活动依赖的信号事件。利用CB1R野生型和空白小鼠，我们将探索CB1R的增强在多大程度上与谷氨酸和GABA能系统的发育有关。我们将评估增强的CB1R功能对活动依赖信号的影响。最后，Aim 3将评估这样一种假设，即出生后酒精引起的神经行为障碍可归因于持续的CB1R活性，并可通过阻断CB1R活性来挽救。我们将使用出生后接触乙醇的青春期小鼠的CB1R拮抗剂处理成年小鼠，评估长时程增强(LTP)、突触超微结构的变化、成年神经发生、社会行为以及学习和记忆。如果成功，这些数据可能会为理解机制打开一扇新的窗口，这些机制可能有助于开发治疗早期乙醇诱导的神经行为异常的潜在治疗策略。

 DESCRIPTION (provided by applicant): Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks that include deficits in learning and memory. Our data during the current funding period revealed a novel function of anandamide (AEA) and the cannabinoid type 1 receptor (CB1R) as a regulator of neurodegeneration (ND) in postnatal ethanol exposed neonatal (postnatal day 7, P7) mice that is associated with synaptic dysfunction in adult mice. In this application, we propose that postnatal ethanol exposure induces persistent enhancement of CB1R function to disrupt synaptic homeostasis and, learning and memory. Although prolonged exposure paradigms might align more closely to common etiologies of FASD, the binge model allows a more precise analysis of mechanisms and thus provides potential therapeutic targets for treatment. Our pilot data with postnatal ethanol models support that the enhanced CB1R activity observed in neonates persists through adulthood and that blocking CB1R long after postnatal ethanol exposure was able to rescue spatial memory deficits in adults. The overreaching objective of this renewal application is to better understand and define the molecular events responsible for the persistent expression of CB1R and its impact on development of the synaptic circuit, activity- dependent signaling, synaptic structure and neurobehavioral abnormalities observed in adult mice. The goal of Aim 1 is to test the hypothesis that postnatal ethanol exposure induces persistent expression of CB1R to adulthood and examine the histone and DNA modification at the CB1R promoter that support enhanced CB1R expression in neocortical and hippocampal structures. Specific Aim 2 will test the hypothesis that postnatal ethanol-induced persistent expression of CB1R disrupts development of the synaptic circuit and neuronal activity-dependent signaling events that might be involved in synaptic activity. Using both CB1R wild type and null mice, we will explore the extent to which the enhancement of CB1R is associated with the development of glutamatergic and GABAergic systems. We will evaluate the effect of enhanced CB1R function on activity-dependent signaling. Finally, Aim 3 will evaluate the hypothesis that postnatal ethanol induced neurobehavioral deficits can be attributed to persistent CB1R activity and can be rescued by blocking CB1R activity. We will evaluate long-term potentiation (LTP), ultrastructural changes in synapses using EM analysis, adult neurogenesis, social behavior, and learning and memory in adult mice treated with a CB1R antagonist from postnatal ethanol exposed adolescent mice. If successful, these data could open a new window into understanding of the mechanisms that might help develop potential therapeutic strategies for treating early ethanol-induced neurobehavioral abnormalities.