PDF(Pubmed)
Abstract：
Background: Altered sensory processing is a pervasive symptom in individuals with Autism Spectrum Disorders (ASD); people with Phelan McDermid syndrome (PMS), in particular, show reduced responses to sensory stimuli. PMS is caused by deletions of the terminal end of chromosome 22 or point mutations in Shank3. People with PMS can present with an array of symptoms including ASD, epilepsy, gastrointestinal distress, and reduced responses to sensory stimuli. People with PMS are often medicated to manage behaviors like aggression and/or self-harm and/or epilepsy, and it remains unclear how these medications might impact perception/sensory processing. Here we test this using zebrafish mutant shank3ab PMS models that likewise show reduced sensory responses in a visual motor response (VMR) assay, in which increased locomotion is triggered by light to dark transitions. Methods: We screened three medications, risperidone, lithium chloride (LiCl), and carbamazepine (CBZ), prescribed to people with PMS and one drug, 2-methyl-6-(phenylethynyl) pyridine (MPEP) tested in rodent models of PMS, for their effects on a sensory-induced behavior in two zebrafish PMS models with frameshift mutations in either the N- or C- termini. To test how pharmacological treatments affect the VMR, we exposed larvae to selected drugs for 24 hours and then quantified their locomotion during four ten-minute cycles of lights on-to-off stimuli. Results: We found that risperidone normalized the VMR in shank3 models. LiCl and CBZ had no effect on the VMR in any of the three genotypes. MPEP reduced the VMR in wildtype (WT) to levels seen in shank3 models but caused no changes in either shank3 model. Finally, shank3 mutants showed resistance to the seizure-inducing drug pentylenetetrazol (PTZ), at a dosage that results in hyperactive swimming in WT zebrafish. Conclusions: Our work shows that the effects of drugs on sensory processing are varied in ways that can be highly genotype- and drug-dependent.
摘要：
背景：感觉过程改变是自闭症谱系障碍（ASD）患者的普遍症状；PhelanMcDermid综合征（PMS）患者，特别是,对感官刺激的反应降低。PMS是由22号染色体末端的缺失或Shank3中的点突变引起的。患有PMS的人可能会出现一系列症状，包括ASD，癫痫,肠胃不适,减少对感官刺激的反应。患有PMS的人通常会接受药物治疗，以管理侵略和/或自我伤害和/或癫痫等行为，目前尚不清楚这些药物如何影响感知/感觉处理。在这里，我们使用斑马鱼突变体shank3abPMS模型进行测试，该模型在视觉运动反应（VMR）测定中同样显示出降低的感觉反应，其中增加的运动是由亮到暗的转变触发的。方法：我们筛选了三种药物，利培酮,氯化锂(LiCl),卡马西平（CBZ），给患有PMS和一种药物的人开处方，2-甲基-6-（苯基乙炔基）吡啶（MPEP）在PMS的啮齿动物模型中测试，它们对两种斑马鱼PMS模型中N-或C-末端移码突变的感觉诱导行为的影响。为了测试药物治疗如何影响VMR，我们将幼虫暴露于选定的药物24小时,然后在4个10分钟的灯光开关刺激周期内量化其运动.结果：我们发现利培酮使shank3模型中的VMR正常化。LiCl和CBZ对三种基因型中任何一种的VMR均无影响。MPEP将野生型（WT）中的VMR降低至shank3模型中可见的水平，但未引起任何shank3模型的变化。最后,shank3突变体对诱发癫痫发作的药物戊四氮（PTZ）具有抗性，剂量会导致WT斑马鱼过度活跃游泳。结论：我们的工作表明，药物对感官加工的影响以高度依赖基因和药物的方式变化。
