Endocannabinoid Signaling in Postnatal Ethanol Effects

 描述（由申请人提供）：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缺陷。我们在当前资助期间的数据揭示了花生四烯酸酰胺（AEA）和大麻素1型受体（CB1R）作为出生后乙醇暴露的新生儿（出生后第7天，P7）小鼠神经变性（ND）的调节剂的新功能，该功能与成年小鼠的突触功能障碍有关。在这个应用中，我们提出，出生后乙醇暴露诱导持续增强CB1R功能，破坏突触稳态，学习和记忆。虽然长期暴露的范例可能更接近FASD的常见病因，但狂欢模型允许更精确的机制分析，从而提供了潜在的治疗靶点。我们的试验数据与出生后乙醇模型支持，增强CB1R活性在新生儿中观察到持续到成年期，并在出生后很长时间内阻断CB1R乙醇暴露能够挽救成人的空间记忆缺陷。该更新申请的过度目标是更好地理解和定义负责CB1R持续表达的分子事件及其对成年小鼠中观察到的突触回路发育、活性依赖性信号传导、突触结构和神经行为异常的影响。目的1的目标是测试的假设，即出生后乙醇暴露诱导持续表达的CB1R到成年期，并检查组蛋白和DNA修饰的CB1R启动子，支持增强CB1R的表达在新皮层和海马结构。具体目标2将测试的假设，出生后乙醇诱导的持续表达的CB1R破坏突触电路和神经元活动依赖性信号事件，可能参与突触活动的发展。使用CB1R野生型和无效小鼠，我们将探讨CB1R的增强与谷氨酸能和GABA能系统的发展相关的程度。我们将评估增强CB1R功能对活性依赖性信号传导的影响。最后，目标3将评估这一假设，即出生后乙醇诱导的神经行为缺陷可归因于持续的CB1R活性，并可通过阻断CB1R活性来挽救。我们将评估长时程增强（LTP），突触超微结构的变化，使用EM分析，成年神经发生，社会行为，学习和记忆与CB1R拮抗剂处理的成年小鼠从出生后乙醇暴露的青春期小鼠。如果成功的话，这些数据可以打开一个新的窗口，了解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的机制。

 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.