Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2011;6(10):e26077. doi: 10.1371/journal.pone.0026077. Epub 2011 Oct 7.
Autism spectrum disorders (ASD) are highly disabling developmental disorders with a population prevalence of 1-3%. Despite a strong genetic etiology, there are no current therapeutic options that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of glutamatergic signaling, in particular through metabotropic glutamate receptor 5 (mGluR5) receptors, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. This study assessed the therapeutic potential of 2-methyl-6-phenylethyl-pyrididine (MPEP), an mGluR5-receptor antagonist, on repetitive and anxiety-like behaviors in the valproic acid (VPA) mouse model of autism. Mice were exposed prenatally on day E13 to VPA and assessed for repetitive self-grooming and marble burying behaviors as adults. Anxiety-like behavior and locomotor activity were measured in an open-field. VPA-exposed mice displayed increased repetitive and anxiety-like behaviors, consistent with previously published results. Across both marble burying and self-grooming assays, MPEP significantly reduced repetitive behaviors in VPA-treated mice, but had no effect on locomotor activity. These results are consistent with emerging preclinical literature that mGluR5-antagonists may have therapeutic efficacy for core symptoms of autism.
自闭症谱系障碍（ASD）是一种高度致残的发育障碍，其人群患病率为 1-3%。尽管存在强烈的遗传病因，但目前尚无针对 ASD 核心症状的治疗方法。新出现的证据表明，谷氨酸能信号传导功能障碍，特别是通过代谢型谷氨酸受体 5（mGluR5）受体，可能导致表型缺陷，并可能成为药物干预的适当靶点。本研究评估了 2-甲基-6-苯乙基-吡啶（MPEP），一种 mGluR5 受体拮抗剂，对自闭症的丙戊酸（VPA）小鼠模型中重复和焦虑样行为的治疗潜力。在 E13 天对怀孕的小鼠进行 VPA 暴露，并在成年后评估其重复自我梳理和埋丸行为。在开阔场中测量焦虑样行为和运动活动。VPA 暴露的小鼠表现出增加的重复和焦虑样行为，与之前发表的结果一致。在埋丸和自我梳理两项测试中，MPEP 均可显著减少 VPA 处理小鼠的重复行为，但对运动活动没有影响。这些结果与新兴的临床前文献一致，即 mGluR5 拮抗剂可能对自闭症的核心症状具有治疗效果。
