Schwamborn Robert, Brown Eric, Haase Jana
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
J Neurochem. 2016 May;137(3):423-35. doi: 10.1111/jnc.13596. Epub 2016 Mar 22.
The serotonin transporter (SERT) is responsible for high-affinity serotonin (5-HT) uptake from extracellular fluid and is a prominent pharmacological target in the treatment of depression. In recent years, depression has also been linked to immune system activation. Inflammatory conditions can cause sickness behaviour and depression-like symptoms in both animals and humans. Since SERT has been proposed as one of the molecular targets in inflammation-induced depression, we applied the widely used lipopolysaccharides (LPS) model to study the effects of peripheral inflammation on SERT activity in the brain. We show that 24 h after intraperitoneal LPS administration, SERT-mediated 5-HT uptake is significantly enhanced in the frontal cortex. Analysis of uptake kinetics revealed that the transport capacity (Vmax ) of cortical SERT was increased in LPS-injected animals, while the Km value remained unchanged. The increase in Vmax was neither due to increased SERT protein expression nor increased synaptic surface exposure. The suppression of SERT activity upon inhibition of p38 MAPK was not selective for LPS-induced enhancement of SERT function. In addition, SERT activity changes in LPS-treated rats are unaffected by nitric oxide synthase and protein kinase G inhibitors. Using the Phos-Tag method, we identified five SERT-specific protein bands representing distinct phosphorylation states of SERT. However, the enhancement of SERT activity in LPS-treated rats was not correlated with altered transporter phosphorylation. Together with previous studies by others, our results suggest that SERT is regulated by multiple mechanisms in response to peripheral immune system activation. Peripheral injection of lipopolysaccharide (LPS) induces characteristic sickness and depression-like behaviour in rats over a period of at least 24 h. We show here that the activity of the serotonin transporter (SERT), a prominent antidepressant target, is up-regulated 24 h following LPS administration. In contrast to previous studies focusing on earlier responses to LPS treatment, we found that SERT function is selectively enhanced in the frontal cortex, independently of the p38 MAPK pathway. Our study provides further insight into molecular mechanisms underlying inflammation-induced depression.
血清素转运体（SERT）负责从细胞外液中高亲和力摄取血清素（5-羟色胺，5-HT），是治疗抑郁症的一个重要药理学靶点。近年来，抑郁症还与免疫系统激活有关。炎症状态可在动物和人类中引发疾病行为和类似抑郁的症状。由于SERT已被认为是炎症诱导型抑郁症的分子靶点之一，我们应用广泛使用的脂多糖（LPS）模型来研究外周炎症对大脑中SERT活性的影响。我们发现，腹腔注射LPS 24小时后，额叶皮质中SERT介导的5-HT摄取显著增强。摄取动力学分析显示，注射LPS的动物皮质SERT的转运能力（Vmax）增加，而米氏常数（Km）值保持不变。Vmax的增加既不是由于SERT蛋白表达增加，也不是由于突触表面暴露增加。抑制p38丝裂原活化蛋白激酶（MAPK）时SERT活性的抑制对LPS诱导的SERT功能增强并无选择性。此外，LPS处理大鼠的SERT活性变化不受一氧化氮合酶和蛋白激酶G抑制剂的影响。使用Phos-Tag方法，我们鉴定出五条代表SERT不同磷酸化状态的SERT特异性蛋白条带。然而，LPS处理大鼠中SERT活性的增强与转运体磷酸化的改变无关。与其他人之前的研究一起，我们的结果表明，SERT在响应外周免疫系统激活时受到多种机制的调节。外周注射脂多糖（LPS）在至少24小时的时间内诱导大鼠出现特征性的疾病和类似抑郁的行为。我们在此表明，作为一个重要抗抑郁靶点的血清素转运体（SERT）的活性在LPS给药后24小时上调。与之前关注对LPS治疗早期反应的研究不同，我们发现SERT功能在额叶皮质中选择性增强，独立于p38 MAPK途径。我们的研究为炎症诱导型抑郁症的分子机制提供了进一步的见解。
