Rationale

Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT_1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT_1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT_1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT_1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969.

Objectives

We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT_1B receptor binding and 5-HT_1B-mediated sensorimotor deficits.

Methods

Specific binding to 5-HT_1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT_1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined.

Results

While enhanced SERT function increased 5-HT_1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum.

Conclusions

While reducing 5-HT_1B receptors may attenuate sensorimotor gating deficits, increased 5-HT_1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.

中文翻译：

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血清素 5-HT 1B 受体介导的行为和与过度活跃和失调的血清素转运蛋白 Ala56 变体的结合

基本原理

升高的全血血清素 (5-HT) 是约 30% 的自闭症谱系障碍患者的强大生物标志物，其中重复行为是核心症状。此外，儿童强迫症患者的全血 5-HT 水平也升高。5-HT _1B受体与两种疾病中的重复行为有关。5-羟色胺转运蛋白 (SERT) 的慢性阻断降低了眶额皮质 (OFC) 中的5-HT _1B受体水平，并减轻了 5-HT _1B激动剂 RU24969所见的感觉运动缺陷和多动症。我们假设增强的 SERT 功能会增加OFC 中的5-HT _1B受体水平并增强由 RU24969 诱导的感觉运动缺陷和多动。

目标

我们检查了导致 SERT 功能增强的 SERT Ala56 突变对 5-HT _1B受体结合和 5-HT _1B介导的感觉运动缺陷的影响。

方法

在幼稚 SERT Ala56 或野生型小鼠的 OFC 和纹状体中测量了与 5-HT _1B受体的特异性结合。检查了 5-HT _1A/1B受体激动剂 RU24969 对惊吓、多动和 cFos 表达的前脉冲抑制 (PPI) 的影响。

结果

虽然增强的 SERT 功能增加了 Ala56 小鼠 OFC 中的5-HT _1B受体水平，但 RU24969 诱导的 PPI 缺陷和过度运动在基因型之间没有差异。cFos 表达的基线水平在各组之间没有差异。RU24969 增加野生型OFC 中的cFos 表达并降低纹状体中的cFos。

结论

虽然减少 5-HT _1B受体可能会减轻感觉运动门控缺陷，但SERT Ala56 小鼠中增加的 5-HT _1B水平并不一定会加剧这些缺陷，这可能是由于该模型系统中神经回路发育过程中的补偿。