5HT transporter & 1A receptor function in BDNF(+/-)mice

5HT转运蛋白

• 批准号: 7105693
• 负责人: JULIE Gorton HENSLER
• 金额: $ 16.43万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105693
• 关键词: G protein; age difference; autoradiography; binding sites; brain derived neurotrophic factor; brain stem; clearance rate; corpus striatum; developmental neurobiology; enzyme linked immunosorbent assay; frontal lobe /cortex; hippocampus; laboratory mouse; mesencephalon; neural transmission; protein protein interaction; protein structure function; serotonin; serotonin inhibitor; serotonin receptor; serotonin transporter

DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) promotes serotonergic neurotransmission and the structural plasticity of serotonergic (5rHT) neurons in the adult brain. Impaired 5-HT function and decreases in BDNF have been implicated in the pathophysiology of major depression and anxiety disorders. However, 5-HT and BDNF neurotransmission may become compromised in aging and therefore play important roles in the pathogenesis of age-related neurodegenerative disorders, as well as depression. This application describes exploratory research characterizing in a BDNF deficient mouse the function of the serotonin transporter (SERT) and somatodendritic 5-HT1A autoreceptor, proteins that play a key role in regulating 5-HT neuro- transmission. BDNF () mice exhibit age-dependent structural and neurochemical deficits in central 5-HT neurons. Prior to the appearance of gross structural deficits, BDNF () mice at 3-6 months of age display region-specific abnormalities in 5-HT neurotransmission, and an attenuation of somatodendritic 5-HT1A autoreceptor function in the median but not dorsal raphe nucleus. Preliminary data indicate that SERT function in the CAS region of hippocampus is markedly attenuated in BDNF () mice at 5, but not 2 months of age when compared to wild-type mice. The techniques employed in the proposed studies, quantitative autoradiography and in vivo high-speed chronoamperometry, offer the anatomical resolution necessary for us to address the hypothesis that in BDNF deficient mice, age-dependent abnormalities in SERT or somatodendritic 5-HT1A autoreceptor function will be observed for the 5-HT neurons arising from the median raphe nucleus. As the striatum receives 5-HT projections arising predominantly from the dorsal raphe nucleus, and the hippocampus receives 5-HT projections arising predominantly from the median raphe nucleus, we will focus on these areas of brain. We will characterize the function of the somatodendritic 5- HT1A autoreceptor (Aim #1) and SERT (Aim #2) in BDNF () versus wild-type mice at three discrete ages: (i) 2 months of age, presumably before the interactive effects of BDNF gene deletion and aging would affect 5-HT function, (ii) 5 months of age, a time-point to coincide with previous studies, and (iii) 10 months of age, before a loss of 5-HT innervation to the forebrain occurs. Region-specific and age-dependent changes in BDNF protein levels will be determined in selected brain regions of wild-type and BDNF () mice (Aim #3).

描述（由申请人提供）：脑衍生的神经营养因子（BDNF）促进了成人大脑中血清素能神经传递和血清素能（5RHT）神经元的结构可塑性。 5-HT功能受损和BDNF的降低与严重抑郁症和焦虑症的病理生理有关。但是，5-HT和BDNF神经传递可能会在衰老中受到损害，因此在与年龄相关的神经退行性疾病的发病机理以及抑郁症中起着重要作用。该应用程序描述了在BDNF缺陷小鼠中表征的探索性研究，羟色胺转运蛋白（SERT）和somatendendritic 5-HT1A自身受体，蛋白质在调节5-HT神经传播方面起关键作用。 BDNF（）小鼠在中央5-HT神经元中表现出年龄依赖性的结构和神经化学缺陷。在出现严重的结构缺陷之前，在5-HT神经传递的3-6个月显示区域特异性异常时，BDNF（）小鼠的体积和somatendendritic 5-HT1A自身受体功能的衰减在中位数但不是背骨核的功能。初步数据表明，与野生型小鼠相比，在5个小鼠的BDNF（）小鼠中，海马CAS区域中的SERT功能显着减弱。拟议的研究，定量自显影术和体内高速年代摄影学中采用的技术提供了我们所需的解剖学解决方案，以解决以下假设：在BDNF缺陷的小鼠中，年龄依赖于年龄依赖性的异常，在塞尔特人或体内的5-HT1A自动纤维中，均具有5-HT1A自身纤维的功能。核。由于纹状体主要由背侧raphe核产生的5-HT投影，海马主要由中位raphe核产生的5-HT投影，我们将重点放在这些大脑的区域上。 We will characterize the function of the somatodendritic 5- HT1A autoreceptor (Aim #1) and SERT (Aim #2) in BDNF () versus wild-type mice at three discrete ages: (i) 2 months of age, presumably before the interactive effects of BDNF gene deletion and aging would affect 5-HT function, (ii) 5 months of age, a time-point to coincide with previous studies, and （iii）10个月大，在失去前脑5-HT神经之前发生。 BDNF蛋白水平的区域特异性和年龄依赖性变化将在野生型和BDNF（）小鼠的选定脑区域（AIM＃3）确定。