Adolescent ethanol exposure and NMDA receptor maturation in cerebellum

青少年乙醇暴露与小脑 NMDA 受体成熟

• 批准号: 7256861
• 负责人: MARY LOU VALLANO
• 金额: $ 7.83万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256861
• 关键词: Adolescent; ethanol; exposure; NMDA; receptor

DESCRIPTION (provided by applicant): Ethanol is the most commonly abused drug in adolescents yet we know very little about its actions in adolescent brain. We seek to understand ethanol effects on the activity-dependent maturation and function of the mammalian cerebellar cortex, which is mediated primarily by the excitatory neurotransmitter glutamate. This is important because the cerebellum has critical roles in motor and cognitive functions, and continues to undergo substantial growth in the adolescent. In particular, N-methyl-D-aspartate receptor (NR) composition and function changes, and ethanol is an antagonist of NRs in many brain regions and neuronal types, including cerebellum. As such, ethanol is predicted to influence NRs themselves as well as signaling cascades that lie downstream of NRs, in particular Ca2+ and calmodulin-dependent kinases in the cytosol and nucleus. We will use a rat model and a combination of molecular biological, immunochemical and anatomical techniques, focusing on NRs and CaMKs in the internal granular layer. We hypothesize that chronic use of ethanol beginning in pre-adolescence will irreversibly interfere with the development and function of the glutamatergic mossy fiber-granule neuron synaptic circuitry and signaling molecules. This will be reflected by specific and persistent alterations in NR2A-C subunit mRNAs and immunoreactive proteins, exon selection in NR1, and maturation of the downstream Ca2+-dependent kinases, CaMKK and CaMKIV. We do not predict substantial cell loss in response to ethanol since death is typically observed when ethanol is administered to neonates at postnatal days 4 -6. Rather, ethanol is expected to interfere with synaptic maturation and therefore, information processing in the adolescent cerebellum. We chose the RO3 mechanism of support because this pilot project will serve as a foundation for future studies exploring the functional consequences of ethanol on cerebellar physiology and pathophysiology. These future studies will be designed with substantial input from our collaborators at Upstate Medical and Binghamton Universities who are established experts in the fields of fetal and adolescent alcohol research. Adolescents consume at least one-fourth of alcohol in this country, yet we understand little about ethanol effects in adolescent brain. The cerebellar cortex, which continues to undergo significant growth and synaptic refinement through adolescence is one of the most sensitive targets of ethanol. We will test the hypothesis that ethanol irreversibly interferes with maturation of excitatory neurotransmitter molecules and their downstream effectors using the rat model. Our results will serve as a basis for future functional studies.

描述（由申请人提供）：乙醇是青少年中最常见的药物，但我们对其在青少年大脑中的作用知之甚少。我们寻求了解乙醇对哺乳动物小脑皮质的活性依赖性成熟和功能的影响，该皮质主要是由兴奋性神经递质谷氨酸介导的。这很重要，因为小脑在运动和认知功能中具有关键作用，并继续在青少年中经历大量增长。特别是，N-甲基-D-天冬氨酸受体（NR）组成和功能变化，乙醇是许多大脑区域和神经元类型（包括小脑）NR的拮抗剂。因此，预测乙醇会影响NRS下游的NR和信号级联反应，尤其是Ca2+和细胞质和核中钙调蛋白依赖性激酶。我们将使用大鼠模型以及分子生物学，免疫化学和解剖技术的组合，重点是内部粒状层中的NRS和CAMK。我们假设在青春期前开始慢性使用乙醇将不可逆地干扰谷氨酸能苔藓纤维颗粒颗粒神经元突触电路和信号分子的发育和功能。 NR2A-C亚基mRNA和免疫反应性蛋白，NR1中的外显子选择以及下游Ca2+依赖性激酶，CAMKK和CAMKIV的成熟。我们不会预测响应乙醇的大量细胞损失，因为在产后第4-6天将乙醇施用到新生儿时，通常会观察到死亡。相反，乙醇有望干扰突触成熟，因此会干扰青少年小脑中的信息处理。我们选择了RO3支持机制，因为该试点项目将成为探索乙醇对小脑生理学和病理生理学的功能后果的未来研究的基础。这些未来的研究将以我们在胎儿和青少年酒精研究领域成立的高级医学和宾厄姆顿大学的合作者的大量投入进行设计。青少年在这个国家消费至少四分之一的酒精，但我们对青少年大脑的乙醇作用一无所知。小脑皮层继续在青春期继续进行显着的生长和突触改进，是乙醇最敏感的靶标之一。我们将检验以下假设：乙醇不可逆地干扰了使用大鼠模型的兴奋性神经递质分子及其下游效应子的成熟。我们的结果将成为未来功能研究的基础。