Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Porter Neuroscience Research Center, Bethesda, MD 20892, USA.
Neuropsychopharmacology. 2010 Mar;35(4):976-89. doi: 10.1038/npp.2009.201. Epub 2009 Dec 23.
Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including well-replicated deficits in reciprocal social interactions and social approach, unusual patterns of ultrasonic vocalization, and high levels of repetitive self-grooming. These phenotypes offer straightforward behavioral assays for translational investigations of pharmacological compounds. Two suggested treatments for autism were evaluated in the BTBR mouse model. Methyl-6-phenylethynyl-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor, blocks aberrant phenotypes in the Fmr1 mouse model of Fragile X, a comorbid neurodevelopmental disorder with autistic features. Risperidone has been approved by the United States Food and Drug Administration for the treatment of irritability, tantrums, and self-injurious behavior in autistic individuals. We evaluated the actions of MPEP and risperidone on two BTBR phenotypes, low sociability and high repetitive self-grooming. Open field activity served as an independent control for non-social exploratory activity and motor functions. C57BL/6J (B6), an inbred strain with high sociability and low self-grooming, served as the strain control. MPEP significantly reduced repetitive self-grooming in BTBR, at doses that had no sedating effects on open field activity. Risperidone reduced repetitive self-grooming in BTBR, but only at doses that induced sedation in both strains. No overall improvements in sociability were detected in BTBR after treatment with either MPEP or risperidone. Our findings suggest that antagonists of mGluR5 receptors may have selective therapeutic efficacy in treating repetitive behaviors in autism.
自闭症是一种神经发育障碍，其特征是异常的互惠社会互动、沟通缺陷以及兴趣受限的重复行为。BTBR T+tf/J（BTBR）是一种近交系小鼠品系，表现出与自闭症的所有三个诊断症状相似的强大行为表型，包括互惠社会互动和社交接近方面的可重复缺陷、异常的超声波发声模式以及高水平的重复自我梳理。这些表型为药理学化合物的转化研究提供了直接的行为测定方法。两种被提议的自闭症治疗方法在 BTBR 小鼠模型中进行了评估。Methyl-6-phenylethynyl-pyridine（MPEP），一种 mGluR5 代谢型谷氨酸受体拮抗剂，可阻断脆性 X 综合征（一种伴有自闭症特征的神经发育障碍）的 Fmr1 小鼠模型中的异常表型。利培酮已被美国食品和药物管理局批准用于治疗自闭症个体的易怒、发脾气和自残行为。我们评估了 MPEP 和利培酮对 BTBR 的两种表型（社交能力低和自我梳理行为高）的作用。开阔场活动作为非社交探索活动和运动功能的独立对照。C57BL/6J（B6），一种社交能力高、自我梳理行为低的近交系，作为品系对照。MPEP 显著降低了 BTBR 的重复自我梳理行为，而对开阔场活动没有镇静作用。利培酮降低了 BTBR 的重复自我梳理行为，但仅在两种品系都引起镇静的剂量下。在用 MPEP 或利培酮治疗后，BTBR 的社交能力均未得到总体改善。我们的发现表明，mGluR5 受体拮抗剂可能在治疗自闭症的重复行为方面具有选择性的治疗效果。
