Animal Models In Serotonin Function and Behavior Effects

5-羟色胺神经递质系统及其关键组件之一--5-羟色胺转运体(SERT)是该项目的主要目标。LCS中SERT基因敲除小鼠的发展为研究SERT和5-羟色胺受体提供了新的活工具，SERT和5-羟色胺受体是世界上使用的数量最多的神经精神药物的靶分子。在5-羟色胺基因敲除小鼠中发现了30多种神经化学、行为和其他表型变化。由此得到的数据有助于指导LCS和其他实验室对最近在人类SERT基因中发现的多种变异进行研究。 我们研究的广泛目标是更好地了解5-羟色胺神经递质系统及其在生理、行为和人类疾病，特别是神经精神疾病中的作用。5-羟色胺几乎参与了所有已知的生理功能。5-羟色胺转运体(SERT)在释放后再循环，从而终止其受体上的作用。 为了更好地了解5-羟色胺的功能，我们建立了一个小鼠模型，它要么缺乏5-羟色胺转运体，要么5-羟色胺转运体的表达减少了50%。SERT-/-和+/-小鼠细胞外液5-羟色胺(5-羟色胺)浓度按基因比例增加。即，+/+小鼠的SERT缺陷分别是+/+小鼠的9倍和5倍，自受孕以来就存在SERT缺陷。 我们的小鼠模型为我们提供了一种活的遗传学工具，可以探索5-羟色胺在正常生理和疾病中的作用。这个小鼠模型提供了一个以前没有的实验窗口来测试关于5-羟色胺在多种生物过程和人类疾病中的作用的假说。我们的小鼠模型也为进一步阐明生理调控机制、神经解剖发育提供了机会。情绪状态和药物效应。 去年报告的SERT基因敲除小鼠攻击性和行为绝望的减少以及类焦虑行为的增加可能是细胞外空间5-羟色胺可获得性增加的结果。这种过量的5-羟色胺的另一个后果是5-HT1a在5-HTT基因敲除小鼠中的表达和功能下降。此外，在过去的一年里，我们报告说，这些小鼠也表现出区域特异性的5-HT2A/C受体表达的改变。杏仁核中的5-HT2A/C受体增加，杏仁核是大脑中与攻击有关的区域。5-羟色胺及其突触前和突触后受体以及相关的细胞内信号通路的作用可能是焦虑和抑郁表达不足的原因。此外，由于5-羟色胺对神经细胞具有营养作用，我们正在研究5-羟色胺转运体和某些神经营养因子(如BDNF)在神经元功能、生存和发育中的作用。我们已经成功地建立了小鼠SERT x BDNF双基因敲除小鼠模型，以进一步研究5-羟色胺转运体和BDNF在神经系统发育中的作用，因为人类遗传学研究分别表明这两个基因与情感障碍的发展有关。

The serotonin neurotransmitter system and one of its key components, the serotonin transporter (SERT), is the primary target of this project. The development of the SERT knockout mouse in the LCS provided a new living tool to study SERT and serotonin receptors, the target molecules for the largest numbers of neuropsychiatric drugs used in the world. 30 plus neurochemical, behavioral and other phenotypic changes have been discovered in the serotonin knockout mouse. The resulting data is helping to guide the LCS and other laboratories in investigations of the multiple variants recently discovered in the human SERT gene. The broad goal of our studies is a better understanding of the serotonin neurotransmitter system and its contributions to physiology, behavior and human disorders, especially neuropsychiatric disorders. Serotonin has been implicated in almost every physiological function known. The serotonin transporter (SERT) recycles seorotonin after its release, thereby terminating the action of seotonin at its receptors. In our attempt to better understand serotonin's function, we have generated a mouse model which either lacks the serotonin transporter or has a 50% reduction in serotonin transporter expression. The SERT -/- and +/- mice have gene-proportionate increases in the extracellular fluid serotonin )5-HT) concentrations. i.e., 9- and 5-fold excesses respectively over +/+ mice, with the SERT deficiency present since conception. Our mouse model provides us with a living genetic tool to explore just what 5-HT does in normal physiology and in disease. This mouse model is providing an experimental window not previously available to test hypotheses about 5-HT's contributions to multiple biological processes and human diseases. Our mouse model also provides an opportunity to further elucidate physiological control mechanisms, neuroanatomical development. emotional states, and drug effects. A reduction of aggression and of behavioral despair and increase in anxiety-like behaviors in the SERT knockout mice reported in the last year may be a result of increased availability of serotonin in the extracellular space. Another consequence of this excess serotonin is a decrease in 5-HT1A expression and function in 5-HTT knockout mice. furthermore, we reported this past year that these mice also show altered expression of 5-HT2A/C receptors in a regionally specific manner. 5-HT2A/C receptors are increased in the amygdala, a brain region associated with aggression. The role of serotonin and its pre- and post- synaptic receptors along with associated intracellular signally pathways may underly the expression of anxiety and depression. In addition, as serotonin has a trophic effect on neuronal cells, we are investigating the role of the serotonin transporter and certain neurotrophic factors such as BDNF in neuronal function, survival, and development. We have successfully developed a mouse SERT x BDNF double knockout mouse model to further investigate the role of the serotonin transporter and BDNF in the developing nervouse system as human genetic studies have separately implicated both genes in the development of affective disorders.