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

描述（由申请人提供）：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BDNF减少与重度抑郁和焦虑障碍的病理生理有关。然而，5-HT和BDNF神经传递可能在衰老过程中受损，因此在与年龄相关的神经退行性疾病以及抑郁症的发病机制中发挥重要作用。本申请描述了在BDNF缺陷小鼠中表征5-羟色胺转运体（SERT）和躯体树突5-HT1A自身受体功能的探索性研究，这些蛋白质在调节5-羟色胺神经传递中起关键作用。BDNF（）小鼠在中枢5-HT神经元中表现出年龄依赖性结构和神经化学缺陷。在出现总体结构缺陷之前，3-6月龄的BDNF（）小鼠在5-HT神经传递中表现出区域特异性异常，并且在中叶核而非中叶背核中出现体树突5-HT1A自身受体功能的衰减。初步数据表明，与野生型小鼠相比，BDNF（）小鼠海马CAS区的SERT功能在5月龄时明显减弱，但在2月龄时没有减弱。所提出的研究中采用的技术，定量放射自显影和体内高速时电流测定法，为我们提供了必要的解剖学分辨率，以解决BDNF缺陷小鼠的假设，在中缝核中产生的5-HT神经元中，观察到SERT或体树突5-HT1A自身受体功能的年龄依赖性异常。由于纹状体接收的5-羟色胺主要来自中缝背核，海马接收的5-羟色胺主要来自中缝中核，我们将重点关注大脑的这些区域。我们将在三个不同的年龄对BDNF（）与野生型小鼠的体树突5- HT1A自身受体（Aim #1）和SERT （Aim #2）的功能进行表征：(i) 2个月大，大概在BDNF基因缺失和衰老的相互作用影响5- ht功能之前，（ii） 5个月大，与之前的研究一致的时间点，以及（iii） 10个月大，在前脑5- ht神经支配丧失之前。将在野生型和BDNF小鼠的选定脑区中确定BDNF蛋白水平的区域特异性和年龄依赖性变化（Aim #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).