GABA/ BZ RECEPTOR EXPRESSION IN A PRECEREBELLAR CIRCUIT

小脑前回路中 GABA/BZ 受体的表达

• 批准号: 2270325
• 负责人: ADRIENNE M FROSTHOLM
• 金额: $ 20.58万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2270325
• 关键词: GABA receptor; autoradiography; benzodiazepine receptor; bicuculline; calcitonin gene related peptide; cerebellar Purkinje cell; cerebral cortex; developmental neurobiology; gamma aminobutyrate; gene induction /repression; genetically modified animals; immunocytochemistry; in situ hybridization; insulinlike growth factor; laboratory mouse; neuroanatomy; neuropharmacology; olivary body; receptor binding; receptor expression; synapses

The aim of this proposal is to examine the cellular interactions underlying changes in the developmental expression of gamma aminobutyric acid/benzodiazepine (GABA-A/BZ) receptor subunit mRNAs and ligand binding sites in the murine inferior olivary nucleus. The GABA-A/BZ receptor is thought to be a pentameric chloride channel comprised of selected alpha, beta, gamma, delta and rho subunits, the majority of which have several isoforms: alpha 1-6, beta 1-4, gamma 1-4 and rho 1-2. We have shown that, of the thirteen subunit variants present in the mammalian central nervous system, the alpha 2-5, beta 3, gamma 1-2 are expressed at significant levels in the inferior olivary nucleus. Two clearly different temporal patterns of GABA-A/BZ receptor subunit mRNA expression were observed: The expression of alpha3, alpha5, beta3 and gamma2 mRNAs was at a peak during perinatal development, followed by rapid downregulation thereafter. Conversely, alpha2, alpha4 and gamma1 mRNA expression was very low, or absent, during early development, and a pronounced increase was observed at the end of the first postnatal weeks Inferior olivary neurons are the primary source of climbing fibers innervating the Purkinje cells of the cerebellar cortex. The timecourse of afferent and efferent olivary connections precisely parallels the GABA-A/BZ receptor subunit changes in olivary neurons: During postnatal week two, olivary climbing fiber innervation of the target Purkinje cell regresses; the number of climbing fiber terminals innervating each Purkinje cell is reduced from greater than 3:1, as observed in neonates, to the 1:1 relationship observed in the adult cerebellar cortex. During the same period, olivary neurons become densely innervated by GABAergic afferents. This raises the possibility that the observed developmental switches in subunit expression may be related to epigenetic factors, such as a reduction in neurotrophic factors from the target Purkinje cell, or to stimulation by GABAergic cells of the deep cerebellar and other afferent nuclei. We will explore the role of a number of possible epigenetic mechanisms which may regulate GABA-A/BZ receptor subunit switching during development. These include the role of efferent and afferent connections, potential neurotrophic factors and increased electrical activity. In addition, the effect of subunit gene- deletion, and the generalizability of the subunit switching phenomenon will be studied.

该建议的目的是检查细胞相互作用 伽马氨基植物发育表达的潜在变化 酸/苯二氮卓（GABA-A/BZ）受体亚基mRNA和配体结合 鼠下橄榄核中的位置。 GABA-A/BZ受体是 被认为是由选定α组成的五聚体氯化物通道 Beta，Gamma，Delta和Rho亚基，其中大多数有几个 同工型：Alpha 1-6，Beta 1-4，Gamma 1-4和Rho 1-2。我们已经表明， 在哺乳动物中央神经中存在的13个亚基变种中 系统，Alpha 2-5，beta 3，伽马1-2在显着表达 下橄榄核的水平。两个明显不同的时间 观察到GABA-A/BZ受体亚基mRNA表达的模式： alpha3，alpha5，beta3和gamma2 mRNA的表达在峰值 围产期发育，随后快速下调。 相反，alpha2，alpha4和gamma1 mRNA表达非常低，或 缺席，在早期开发期间观察到明显增加 在出生后第一周结束时，下橄榄神经元是 攀爬纤维的主要来源 小脑皮质。传入和传出橄榄的时间 连接完全与GABA-A/BZ受体亚基相似 橄榄神经元：在产后第二周，橄榄攀登纤维 靶Purkinje细胞的神经支配回归；攀登数量 支撑每个浦肯野细胞的纤维末端从更大的 如在新生儿中观察到的比3：1比在1：1的关系中观察到的 成人小脑皮层。在同一时期，橄榄神经元变成 由GABA能传入密度支配。这增加了可能性 亚基表达中观察到的发育开关可能是 与表观遗传因素有关，例如降低神经营养因素 从靶Purkinje细胞或通过GABA能细胞刺激 小脑和其他传入核。我们将探讨一个角色 可能调节GABA-A/BZ的可能表观遗传机制的数量 受体亚基在开发过程中切换。这些包括 传出和传入的联系，潜在的神经营养因素和 增加电活动。另外，亚基基因的作用 删除和亚基转换现象的普遍性 将被研究。