Institute of Biomedicine/Physiology, University of Helsinki Helsinki, Finland.
Neuroscience Center, University of Helsinki Helsinki, Finland.
Front Cell Neurosci. 2014 May 28;8:150. doi: 10.3389/fncel.2014.00150. eCollection 2014.
Fluoxetine is used as a therapeutic agent for autism spectrum disorder (ASD), including Fragile X syndrome (FXS). The treatment often associates with disruptive behaviors such as agitation and disinhibited behaviors in FXS. To identify mechanisms that increase the risk to poor treatment outcome, we investigated the behavioral and cellular effects of fluoxetine on adult Fmr1 knockout (KO) mice, a mouse model for FXS. We found that fluoxetine reduced anxiety-like behavior of both wild-type and Fmr1 KO mice seen as shortened latency to enter the center area in the open field test. In Fmr1 KO mice, fluoxetine normalized locomotor hyperactivity but abnormally increased exploratory activity. Reduced brain-derived neurotrophic factor (BDNF) and increased TrkB receptor expression levels in the hippocampus of Fmr1 KO mice associated with inappropriate coping responses under stressful condition and abolished antidepressant activity of fluoxetine. Fluoxetine response in the cell proliferation was also missing in the hippocampus of Fmr1 KO mice when compared with wild-type controls. The postnatal mRNA expression of serotonin transporter (SERT) was reduced in the thalamic nuclei of Fmr1 KO mice during the time of transient innervation of somatosensory neurons suggesting that developmental changes of SERT expression were involved in the differential cellular and behavioral responses to fluoxetine in wild-type and Fmr1 mice. The results indicate that changes of BDNF/TrkB signaling contribute to differential behavioral responses to fluoxetine among individuals with ASD.
氟西汀被用作自闭症谱系障碍（ASD）的治疗药物，包括脆性 X 综合征（FXS）。这种治疗方法常与 FXS 患者的激越和去抑制行为等破坏性行为相关。为了确定增加治疗效果不佳风险的机制，我们研究了氟西汀对成年 Fmr1 敲除（KO）小鼠的行为和细胞效应，该小鼠模型用于 FXS。我们发现氟西汀减少了野生型和 Fmr1 KO 小鼠的焦虑样行为，表现在旷场试验中进入中央区域的潜伏期缩短。在 Fmr1 KO 小鼠中，氟西汀使运动过度正常化，但异常增加了探索性活动。Fmr1 KO 小鼠海马中的脑源性神经营养因子（BDNF）减少和 TrkB 受体表达水平增加与应激条件下的不当应对反应有关，并消除了氟西汀的抗抑郁作用。与野生型对照相比，Fmr1 KO 小鼠海马中的细胞增殖对氟西汀的反应也缺失了。在感觉神经元短暂支配期间，Fmr1 KO 小鼠丘脑核中的 5-羟色胺转运体（SERT）的产后 mRNA 表达减少，这表明 SERT 表达的发育变化参与了野生型和 Fmr1 小鼠对氟西汀的细胞和行为反应的差异。结果表明，BDNF/TrkB 信号的变化导致 ASD 个体对氟西汀的反应存在差异。
