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^Met/Met 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（例如焦虑症）发病率达到顶峰的发育阶段。选择性血清素再摄取抑制剂（SSRI）是用于治疗焦虑症的主要药物类别。然而，SSRIs 对青春期大脑发育的影响仍不清楚。作者评估了在表现出焦虑样行为升高的基因小鼠模型中按发育时间进行 SSRI 给药的影响。

脑源性神经营养因子（BDNF）中含有常见的人类单核苷酸多态性（Val66Met；rs6265），这是一种与 SSRIs 作用机制有关的生长因子，基于其已确定的焦虑增加表型，对敲入小鼠进行了研究。喜欢的行为。氟西汀的定时给药在三个发育时期之一（出生后 21-42 天、40-61 天或 60-81 天）进行，跨越从童年到成年的过渡。进行了神经化学和焦虑样行为分析。

我们确定了青春期期间（出生后 21-42 天）的“敏感期”，其中发育定时的氟西汀给药可挽救成年期 BDNF Val66Met 小鼠的焦虑样表型。与同窝对照相比，BDNF ^Met/Met小鼠表现出特别是前额皮质的血清素能纤维的成熟度降低，以及中缝背侧血清素能营养因子 S100B 的表达降低。有趣的是，青春期期间服用氟西汀可以挽救血清素能神经支配以及 S100B 水平不足的情况。

这些发现表明，在青春期“敏感期”服用 SSRI 可在焦虑样行为升高的遗传小鼠模型中产生持久的抗焦虑作用。这些持久的作用凸显了 BDNF 在血清素系统成熟中的作用以及通过药物干预增强其发育的能力。