Postnatal Development of Ionotropic Glutamate Receptors

离子型谷氨酸受体的产后发育

• 批准号: 6878016
• 负责人: HENRYK F URBANSKI
• 金额: $ 25.04万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878016
• 关键词: Macaca mulatta; RNase protection assay; age difference; animal puberty; brain mapping; developmental genetics; developmental neurobiology; estradiol; gender difference; gene environment interaction; glutamate receptor; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; infant animal; juvenile animal; luteinizing hormone; neural plasticity; neuroendocrine system; neurogenetics; neurons; neurotransmitters; ovariectomy; protein structure function; sex hormones; testosterone

L-glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system. It plays a major role in behavioral processes such as learning and memory, and is a key component of the neuroendocrine mechanism that controls sexual maturation. Although ionotropic glutamate receptors have been studied extensively in the rodent brain, both at the molecular and pharmacological levels, the postnatal ontogeny of these receptors in humans is poorly understood. To help resolve this issue, the proposed studies will use sexually immature male and female rhesus macaques (Macaca mulatta) to test various hypotheses regarding: 1) the temporal expression of genes encoding different glutamate receptor subunits, 2) the neurotransmitter identity of neurons that show developmental plasticity in glutamate receptor gene expression, and 3) the influence of the changing sex steroid environment on the induction of these developmental receptor changes. The studies will involve a series of molecular and immunohistochemical approaches to characterize and quantify glutamate receptor gene expression at three key stages of postnatal development: 1) infantile, 2) juvenile, and 3) peripubertal, both with and without experimental manipulation of circulating estradiol and testosterone concentrations. Because macaques and humans show similar postnatal cognitive developments and similar developmental changes in their sex-steroid environment, the proposed studies are expected to yield new information about the ontogeny of ionotropic glutamate receptors in humans. Moreover, because the subunit composition of different glutamate receptors determines their affinity for different ligands (e.g., NMDA, AMPA and kainate) and influences their functional properties (e.g., permeability to Ca2+), elucidation of the mechanisms that regulate their developmental expression should help to lay a foundation for the development of pharmacological treatments for pediatric neurological disorders.

L-谷氨酸是哺乳动物中枢神经系统中最丰富的兴奋性神经递质。 它在学习和记忆等行为过程中发挥着重要作用，是控制性成熟的神经内分泌机制的关键组成部分。 尽管离子型谷氨酸受体已在啮齿动物大脑中在分子和药理学水平上进行了广泛的研究，但对人类这些受体的出生后个体发育知之甚少。 为了帮助解决这个问题，拟议的研究将使用性成熟的雄性和雌性恒河猴（Macaca mulatta）来测试以下各种假设：1）编码不同谷氨酸受体亚基的基因的时间表达，2）神经元的神经递质身份谷氨酸受体基因表达的发育可塑性，以及 3) 性类固醇环境变化对诱导这些发育受体变化的影响。 这些研究将涉及一系列分子和免疫组织化学方法，以表征和量化出生后发育的三个关键阶段的谷氨酸受体基因表达：1）婴儿期，2）青少年期，3）青春期前后，无论是否进行循环雌二醇和睾酮浓度。 由于猕猴和人类在性类固醇环境中表现出相似的出生后认知发展和相似的发育变化，因此拟议的研究有望产生有关人类离子型谷氨酸受体个体发育的新信息。 此外，由于不同谷氨酸受体的亚基组成决定了它们对不同配体（例如，NMDA、AMPA和红藻氨酸）的亲和力并影响它们的功能特性（例如，对Ca2+的渗透性），阐明调节它们发育表达的机制应该有助于为小儿神经系统疾病药物治疗的发展奠定基础。