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起着重要作用，并且是控制性成熟的神经内分泌机制的关键组成部分。 尽管已经在啮齿动物的大脑中广泛研究了离子型谷氨酸受体，但无论是在分子和药理水平上，这些受体在人类中的产后个体发育均发育良好。 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这些发育受体改变。 该研究将涉及一系列分子和免疫组织化学方法，以在产后发育的三个关键阶段表征和量化谷氨酸受体基因表达：1）婴儿，2）少年和3）彼得伯伯尔群，无论是在循环雌激素和睾丸激素浓度的实验性操纵时，都需要进行围角菌。 由于猕猴和人类表现出类似的产后认知发展和性类替代环境中的类似发育变化，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，因为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和海藻酸盐）的亲和力，并影响其功能特性（例如，渗透性对Ca2+），阐明其机制的机制，以使其发育表达的机制有助于将其开发用于药物治疗，以进行药物的发展。