5HT transporter & 1A receptor function in BDNF mice

描述(申请人提供)：脑源性神经营养因子(BDNF)促进成人大脑中5-羟色胺能神经传递和5-羟色胺能(5rHT)神经元的结构可塑性。5-羟色胺功能受损和脑源性神经营养因子的减少与抑郁症和焦虑症的病理生理学有关。然而，5-羟色胺和脑源性神经营养因子的神经传递可能会随着年龄的增长而受损，因此在老年性神经退行性疾病和抑郁症的发病机制中发挥着重要作用。这项申请描述了在BDNF缺陷小鼠中5-羟色胺转运体(SERT)和躯体树突状细胞5-HT1A自身受体的功能的探索性研究，这两种蛋白质在调节5-羟色胺神经传递中发挥关键作用。BDNF()小鼠表现出中枢5-羟色胺神经元的年龄依赖性结构和神经化学缺陷。在出现大体结构缺陷之前，3-6月龄BDNF()小鼠表现出5-羟色胺(5-HT)神经传递的区域性异常，中缝正中核(而不是中缝背核)的体树突状5-HT1a自身受体功能减弱。初步数据显示，与野生型小鼠相比，5个月大的BDNF()小鼠海马区SERT功能明显减弱，但不是2个月大的小鼠。在拟议的研究中使用的技术，定量放射自显影和体内高速计时电流测量，为我们提供了必要的解剖学分辨率，以解决以下假设：在BDNF缺陷的小鼠中，来自中缝正中核的5-羟色胺能神经元的SERT或躯体树突状细胞5-HT1A自身受体功能将观察到年龄相关性异常。由于纹状体接受主要来自中缝背核的5-羟色胺投射，而海马体接受主要来自中缝正中核的5-羟色胺投射，我们将重点关注大脑的这些区域。我们将在BDNF()和野生型小鼠中研究躯体树突状5-HT1A自身受体(Aim#1)和SERT(Aim#2)的功能，并在三个不同的年龄组进行比较：(I)2个月龄，推测在BDNF基因缺失和衰老的交互作用会影响5-羟色胺功能之前；(Ii)5个月龄，与以前的研究一致；以及(Iii)10个月龄，在失去前脑的5-HT神经支配之前。将在野生型和BDNF()小鼠的选定大脑区域中确定特定区域和年龄相关的BDNF蛋白水平的变化(目标3)。

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).