Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes.
Knockout of NMDA receptors in parvalbumin interneurons recreates autism-like phenotypes.
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DOI：
10.1002/aur.1264
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发表时间：
2013-04
期刊：
影响因子：
4.7
通讯作者：
Siegel, Steven J.
中科院分区：
文献类型：
--
作者：
Saunders, John A.;Tatard-Leitman, Valerie M.;Suh, Jimmy;Billingslea, Eddie N.;Roberts, Timothy P.;Siegel, Steven J.
自闭症是一种致残性神经发育障碍，其特征是社交缺陷，语言障碍和重复行为，几乎没有有效的治疗方法。新的证据表明，自闭症有可靠的电生理内表型，这些措施可能是由N-甲基-D-天冬氨酸受体（NMDAR）破坏小白蛋白（PV）的中间神经元。这些发现可用于创建新的翻译生物标志物。最近的发展已经允许细胞类型选择性敲除NMDAR，以检查由破坏特定回路引起的扰动。本研究通过选择性减少NMDA R1亚基，检查了自闭症患者的几项电生理和行为测量结果。记录小鼠对听觉刺激的脑电图（EEG）。事件相关电位（ERP）成分振幅和潜伏期分析，社会测试，和交配前超声发声（USVs）记录进行。ERP潜伏期和行为指标之间的相关性进行了研究。与野生型小鼠相比，PV选择性NMDA受体1敲除（NR 1 KO）小鼠的N1 ERP潜伏期延迟，社交能力降低，交配USVs受损。N1潜伏期与社交能力显著相关，但与交配前USV功率或T-迷宫成绩无显著相关。PV选择性NR 1 KO小鼠的N1潜伏期增加、社交能力受损和发声减少，与自闭症中发现的类似变化相似。电生理变化与社交能力降低相关，表明控制N1潜伏期的局部回路机制可能在社交功能中被利用。因此，我们建议PV选择性NR 1基因敲除小鼠的行为和电生理改变可以作为自闭症治疗发展的有用模型。
Autism is a disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors with few effective treatments. New evidence suggests that autism has reliable electrophysiological endophenotypes and that these measures may be caused by n-methyl-d-aspartic acid receptor (NMDAR) disruption on parvalbumin (PV)-containing interneurons. These findings could be used to create new translational biomarkers. Recent developments have allowed for cell-type selective knockout of NMDARs in order to examine the perturbations caused by disrupting specific circuits. This study examines several electrophysiological and behavioral measures disrupted in autism using a PV-selective reduction in NMDA R1 subunit. Mouse electroencephalograph (EEG) was recorded in response to auditory stimuli. Event-related potential (ERP) component amplitude and latency analysis, social testing, and premating ultrasonic vocalizations (USVs) recordings were performed. Correlations were examined between the ERP latency and behavioral measures. The N1 ERP latency was delayed, sociability was reduced, and mating USVs were impaired in PV-selective NMDA Receptor 1 Knockout (NR1 KO) as compared with wild-type mice. There was a significant correlation between N1 latency and sociability but not between N1 latency and premating USV power or T-maze performance. The increases in N1 latency, impaired sociability, and reduced vocalizations in PV-selective NR1 KO mice mimic similar changes found in autism. Electrophysiological changes correlate to reduced sociability, indicating that the local circuit mechanisms controlling N1 latency may be utilized in social function. Therefore, we propose that behavioral and electrophysiological alterations in PV-selective NR1 KO mice may serve as a useful model for therapeutic development in autism.
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影响因子：
4.9
作者：
Gogolla, Nadine;LeBlanc, Jocelyn J.;Quast, Kathleen B.;Sudhof, Thomas C.;Fagiolini, Michela;Hensch, Takao K.
通讯作者：
Hensch, Takao K.
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