Dincheva Iva, Yang Jianmin, Li Anfei, Marinic Tina, Freilingsdorf Helena, Huang Chienchun, Casey B J, Hempstead Barbara, Glatt Charles E, Lee Francis S, Bath Kevin G, Jing Deqiang
From the Departments of Psychiatry, Pharmacology, and Medicine and the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, Cornell University, New York; the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi, China; the Department of Psychology, Yale University, New Haven, Conn.; and the Department of Psychology, Brown University, Providence, R.I.
Am J Psychiatry. 2017 Dec 1;174(12):1203-1213. doi: 10.1176/appi.ajp.2017.15121592. Epub 2017 Oct 31.
Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors.
Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed.
We identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNF mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence.
These findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.
青春期是精神疾病（如焦虑症）发病率达到峰值的发育阶段。选择性5-羟色胺再摄取抑制剂（SSRI）是用于治疗焦虑症的主要药物类别。然而，SSRI在青春期对发育中的大脑的影响仍不清楚。作者在一个表现出焦虑样行为增加的基因小鼠模型中评估了按发育时间给药SSRI的影响。
基于已确定的焦虑样行为增加的表型，研究了脑源性神经营养因子（BDNF）中含有常见人类单核苷酸多态性（Val66Met；rs6265）的敲入小鼠，BDNF是一种与SSRI作用机制有关的生长因子。在从童年到成年的三个发育阶段（出生后第21 - 42天、40 - 61天或60 - 81天）之一期间定时给予氟西汀。进行了神经化学和焦虑样行为分析。
我们确定了青春期前后（出生后第21 - 42天）的一个“敏感期”，在此期间按发育时间给予氟西汀可挽救成年BDNF Val66Met小鼠的焦虑样表型。与同窝对照相比，BDNF小鼠投射到前额叶皮质的5-羟色胺能纤维成熟减少，以及中缝背核中5-羟色胺能营养因子S100B的表达降低。有趣的是，在青春期前后给予氟西汀可挽救5-羟色胺能神经支配不足以及S100B水平。
这些发现表明，在青春期前后的“敏感期”给予SSRI可在焦虑样行为增加的基因小鼠模型中产生持久的抗焦虑作用。这些持久效应突出了BDNF在5-羟色胺系统成熟中的作用以及通过药物干预增强其发育的能力。
