Lesch K P, Mössner R
Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, Füchsleinstr. 15, 97080 Würzburg, Germany.
Handb Exp Pharmacol. 2006(175):417-56. doi: 10.1007/3-540-29784-7_18.
Animal models have not only become an essential tool for investigating the neurobiological function of genes that are involved in the etiopathogenesis of human behavioral and psychiatric disorders but are also fundamental in the development novel therapeutic strategies. As an example, inactivation of the serotonin (5HT) transporter (5Htt, Slc6a4) gene in mice expanded our view of adaptive 5HT uptake regulation and maintenance of 5HT homeostasis in the developing human brain and molecular processes underlying anxiety-related traits, as well as affective spectrum disorders including depression. 5Htt-deficient mice have been employed as a model complementary to direct studies of genetically complex traits and disorders, with important findings in biochemical, morphological, behavioral, and pharmacological areas. Based on growing evidence for a critical role of the 5HTT in the integration of synaptic connections in the rodent, nonhuman primate, and human brain during critical periods of development and adult life, more in-depth knowledge of the molecular mechanisms implicated in these fine-tuning processes is currently evolving. Moreover, demonstration of a joint influence of the 5HTT variation and environmental sources during early brain development advanced our understanding of the mechanism of genexgene and genexenvironment interactions in the developmental neurobiology of anxiety and depression. Lastly, imaging techniques, which become increasingly elaborate in displaying the genomic influence on brain system activation in response to environmental cues, have provided the means to bridge the gap between small effects of 5HTT variation and complex behavior, as well as psychopathological dimensions. The combination of elaborate genetic, epigenetic, imaging, and behavioral analyses will continue to generate new insight into 5HTT's role as a master control gene of emotion regulation.
动物模型不仅已成为研究参与人类行为和精神疾病病因发病机制的基因神经生物学功能的重要工具，而且在开发新的治疗策略方面也至关重要。例如，小鼠中血清素（5HT）转运体（5Htt，Slc6a4）基因的失活，拓宽了我们对发育中的人类大脑中适应性5HT摄取调节和5HT稳态维持以及与焦虑相关特征及包括抑郁症在内的情感谱系障碍潜在分子过程 的认识。5Htt基因缺陷小鼠已被用作一种模型，以补充对遗传复杂性状和疾病的直接研究，并在生物化学、形态学、行为学和药理学领域取得了重要发现。基于越来越多的证据表明5HTT在啮齿动物、非人灵长类动物和人类大脑发育关键期及成年期突触连接整合中起关键作用，目前人们对这些微调过程所涉及的分子机制有了更深入的了解。此外，5HTT变异与早期大脑发育过程中环境因素的联合影响的证明，深化了我们对焦虑和抑郁症发育神经生物学中基因-基因和基因-环境相互作用机制的理解。最后，成像技术在显示基因组对响应环境线索的大脑系统激活的影响方面越来越精细，它提供了弥合5HTT变异的微小影响与复杂行为以及精神病理学维度之间差距的方法。精细的遗传、表观遗传、成像和行为分析相结合，将继续为深入了解5HTT作为情绪调节主控基因的作用带来新的见解。
