Sert Expression and Survival of Serotonin Neurons

血清素神经元的 Sert 表达和存活

• 批准号: 6733543
• 负责人: ANNE MILASINCIC ANDREWS
• 金额: $ 6.9万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-11 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6733543
• 关键词: acetylcholine; aging; antibody; choline acetyltransferase; dopamine; gene expression; genetically modified animals; high performance liquid chromatography; immunocytochemistry; innervation; laboratory mouse; neural degeneration; neurochemistry; neuropathology; norepinephrine; serotonin; serotonin transporter; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): An age-dependent decline in serotonergic innervation of the forebrain has been well documented and may contribute to late onset neurodegenerative disorders, increased incidence of depression or loss of cognitive function that occur with age in humans. This proposal will investigate the relationship between long-term elevations in synaptic serotonin and age and their effects on neuronal innervation in mice with a genetic inactivation of the serotonin transporter gene. Our recent studies indicate that decreased serotonin transporter expression results in a reversal or prevention of normal age-related degeneration of serotonergic axons. We hypothesize that increased extracellular serotonin may be functioning as a trophic factor to promote the survival of serotonergic axons in the forebrain. Mice that lack the serotonin transporter display a 5-fold increase in extracellular serotonin compared to wild type mice. In mice with a 50% reduction in serotonin transporter expression, a 5-fold increase in extracellular serotonin has been detected. In fact, 70% of the normal human population expresses approximately 30% less serotonin transporter, so these findings will have direct applicability to aging in humans. We will investigate the effect decreased serotonin transporter expression on the survival and integrity of forebrain serotonergic, catecholaminergic and cholinergic axons by immunocytochemistry. In addition, we will evaluate the age-related effects of reduced serotonin transporter expression on regional serotonin, dopamine, norepinephrine and acetylcholine neurotransmitter levels. These studies have been designed to integrate anatomical and neurochemical data to assess age-related changes in axonal innervation across the lifespan resulting from decreased of the serotonin transporter expression.

描述（由申请人提供）：前脑血清素神经支配的年龄依赖性下降已被充分证明，并且可能导致迟发性神经退行性疾病、抑郁症发病率增加或随着人类年龄的增长而发生的认知功能丧失。该提案将研究突触血清素长期升高与年龄之间的关系及其对血清素转运蛋白基因失活小鼠神经元神经支配的影响。我们最近的研究表明，血清素转运蛋白表达的减少可以逆转或预防血清素能轴突的正常年龄相关退化。我们假设细胞外血清素的增加可能作为营养因子发挥作用，促进前脑中血清素能轴突的存活。与野生型小鼠相比，缺乏血清素转运蛋白的小鼠的细胞外血清素增加了 5 倍。在血清素转运蛋白表达减少 50% 的小鼠中，检测到细胞外血清素增加了 5 倍。事实上，70% 的正常人群表达的血清素转运蛋白大约减少 30%，因此这些发现将直接适用于人类衰老。我们将通过免疫细胞化学研究血清素转运蛋白表达减少对前脑血清素能、儿茶酚胺能和胆碱能轴突的存活和完整性的影响。此外，我们将评估血清素转运蛋白表达减少对区域血清素、多巴胺、去甲肾上腺素和乙酰胆碱神经递质水平的年龄相关影响。这些研究旨在整合解剖学和神经化学数据，以评估由于血清素转运蛋白表达减少而导致的整个生命周期中与年龄相关的轴突神经支配变化。

项目成果

The neurotoxin 2'-NH2-MPTP degenerates serotonin axons and evokes increases in hippocampal BDNF.

神经毒素 2-NH2-MPTP 使血清素轴突退化并引起海马 BDNF 增加。

• DOI: 10.1016/j.neuropharm.2005.09.006
• 发表时间: 2006
• 期刊: Neuropharmacology.
• 作者: Luellen,BethA;Szapacs,MatthewE;Materese,ChristopherK;Andrews,AnneM
• 通讯作者: Andrews,AnneM

Neuronal and astroglial responses to the serotonin and norepinephrine neurotoxin: 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine.

神经元和星形胶质细胞对血清素和去甲肾上腺素神经毒素的反应：1-甲基-4-(2-氨基苯基)-1,2,3,6-四氢吡啶。

• DOI: 10.1124/jpet.103.055749
• 发表时间: 2003
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Luellen,BethA;Miller,DianeB;Chisnell,AngelaC;Murphy,DennisL;O'Callaghan,JamesP;Andrews,AnneMilasincic
• 通讯作者: Andrews,AnneMilasincic