ELEMENTAL AND STRUCTURAL ORGANIZATION OF NEURONS AND GLIA

神经元和神经胶质细胞的基本和结构组织

• 批准号: 6111844
• 负责人: S BRIAN Andrews
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6111844
• 关键词: Anura; cAMP response element binding protein; calcium flux; confocal scanning microscopy; dendrites; developmental genetics; developmental neurobiology; electron microscopy; electrophysiology; endoplasmic reticulum; estradiol; gamma aminobutyrate; gene expression; glia; hippocampus; hormone regulation /control mechanism; intracellular transport; mitochondria; nerve /myelin protein; neurons; organ culture; protein biosynthesis; protein transport; synapses

This project studies the physiology and development of calcium regulation during neuronal activity, with special emphasis on the dendrites and dendritic spines of central nervous system neurons. Previously, Ca imaging and analytical studies on dendrites of CA3 neurons in hippocampal slice cultures had characterized a subset of endoplasmic reticulum (ER) as the major calcium-sequestering organelle in the time frame of seconds to 15 minutes following afferent synaptic activity. In contrast, mitochondrial calcium uptake operates in parallel with ER sequestration only over the first minute following synaptic activity. A new study reveals a different mode of Ca sequestration in sympathetic neurons. In these neurons, measurements of total Ca (x-ray microanalysis) in parallel with recordings of free cytosolic Ca2+ transients (fura- 2), following depolarizations that evoke defined Ca2+ transients, provide direct evidence for sustained (up to 5 min) and robust calcium sequestration within mitochondria, while ER Ca was little changed. This mitochondrial Ca accumulation is large, time dependent (more than 10 mmol/kg total Ca concentration after a 45 sec depolarization), reversible and sensitive to agents that disrupt mitochondrial transport pathways. Previously we had shown that estradiol doubles dendritic spine density of hippocampal neurons via its effect on inhibitory hippocampal interneurons. These results provided an attractive explanation for the observation that estrogen affects cognition and plasticity in adult organisms. New studies with hippocampal neurons in culture reveal that brain-derived neurotrophic factor (BDNF), which has been implicated in the regulation of GABAergic neurons, is downregulated by 40% following estradiol treatment. This, in turn, increases excitatory tone in these neurons, leading to a twofold increase in spines. These observations reveal a functional link between estradiol and BDNF (as a regulator of GABAergic interneurons) in the activity-dependent enhancement of dendritic spines.

该项目研究生理学和发育 神经元活动期间的钙调节，具有特殊的作用 强调中枢神经的树突和树突棘 系统神经元。此前，Ca 成像和分析研究 海马切片培养物中 CA3 神经元的树突 将内质网 (ER) 的一个子集描述为主要的 钙螯合细胞器在几秒到 15 秒的时间内 传入突触活动后几分钟。相比之下， 线粒体钙摄取与 ER 并行运作 仅在突触活动后的第一分钟内隔离。 一项新的研究揭示了钙螯合的不同模式 交感神经元。在这些神经元中，总 Ca 的测量 （X 射线微量分析）与游离胞质记录并行 Ca2+ 瞬变 (fura- 2)，继引起去极化 定义的 Ca2+ 瞬变，为持续（向上）提供直接证据 至5分钟）和线粒体内强大的钙隔离， 而 ER Ca 变化不大。这种线粒体钙 积累量大，且与时间相关（总计超过 10 mmol/kg 45 秒去极化后的 Ca 浓度），可逆且 对破坏线粒体运输途径的药物敏感。 之前我们已经证明雌二醇使树突棘加倍 海马神经元密度通过其对抑制的影响 海马中间神经元。这些结果提供了一个有吸引力的 对雌激素影响认知的观察结果的解释 成体有机体的可塑性。海马体的新研究 培养中的神经元揭示脑源性神经营养因子 (BDNF)，与 GABA 能的调节有关 雌二醇治疗后神经元的表达下调 40%。 这反过来又增加了这些神经元的兴奋性，从而导致 刺增加两倍。这些观察揭示了功能性 雌二醇和 BDNF 之间的联系（作为 GABA 能调节剂） 中间神经元）在树突的活动依赖性增强中 刺。