Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome
Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome
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DOI：
10.1016/j.nbd.2016.02.002
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发表时间：
2016-05-01
影响因子：
6.1
通讯作者：
Razak, Khaleel A.
中科院分区：
文献类型：
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作者：
Lovelace, Jonathan W.;Wen, Teresa H.;Razak, Khaleel A.
感觉处理缺陷在自闭症谱系障碍中很常见，但其潜在机制尚不清楚。脆性X综合征（FXS）是智力残疾和自闭症的主要遗传原因。FXS患者的电生理反应表现出对声音重复的习惯性降低，这种缺陷可能是FXS听觉超敏反应的基础。我们先前在Fmrl基因敲除（KO）小鼠中的研究揭示了听觉皮层神经元中声音驱动兴奋性增加的异常长状态，这表明皮层对重复声音的反应可能表现出与FXS患者一样的异常习惯化。在这里，我们通过比较野生型（WT）和Fmr 1 KO小鼠记录的皮层事件相关电位（ERP）来测试这一预测。我们报告了一个重复率依赖性减少习惯的N1振幅在Fmr 1基因敲除小鼠和显示，基质金属蛋白酶-9（MMP-9），一个已知的FMRP的目标，有助于减少ERP习惯。我们的研究表明，一个显着的上调MMP-9水平在成年Fmr 1基因敲除小鼠的听觉皮层，而Mmp-9的基因缺失逆转ERP习惯性缺陷的Fmr 1基因敲除小鼠。尽管Mmp-9/Fmr 1 DKO记录的N1振幅大于WT和KO记录，但Mmp-9/Fmr 1 DKO小鼠中ERP的习惯化与WT小鼠相似，暗示MMP-9是逆转FXS中感觉处理缺陷的潜在靶点。这些数据一起建立ERP习惯化作为翻译相关的，生理学的临床前标记的听觉处理缺陷在FXS和表明，异常MMP-9调节是一种机制，潜在的听觉超敏反应在FXS.Significance：脆性X综合征（FXS）是自闭症谱系障碍的领先已知的遗传原因。FXS患者表现出听觉过敏症状。这些症状可能是由于对重复声音的持续神经反应引起的，但其潜在机制仍不清楚。这项研究第一次表明，在FXS患者中观察到的Fmr 1 KO小鼠对重复声音的神经反应习惯化缺陷。我们还报告了一个。在Fmr 1 KO小鼠的听觉皮层中异常高水平的基质金属蛋白酶-9（MMP-9），并且从Fmr 1 KO小鼠中缺失Mmp-9逆转习惯性缺陷。这些数据为FXS中的感觉缺陷提供了翻译相关的电生理生物标志物，并暗示MMP-9是药物发现的靶点。(C)2016 Elsevier Inc. All rights reserved.
Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmrl knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase-9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS.Significance: Fragile X.Syndrome (FXS) is the leading known genetic cause of autism spectrum disorders. Individuals with FXS show symptoms of auditory hypersensitivity. These symptoms may arise due to sustained neural responses to repeated sounds, but the underlying mechanisms remain unclear. For the first time, this study shows deficits in habituation of neural responses to repeated sounds in the Fmr1 KO mice as seen in humans with FXS. We also report an. abnormally high level of matrix metalloprotease-9 (MMP-9) in the auditory cortex of Fmr1 KO mice and that deletion of Mmp-9 from Fmr1 KO mice reverses habituation deficits. These data provide a translation relevant electrophysiological biomarker for sensory deficits in FXS and implicate MMP-9 as a target for drug discovery. (C) 2016 Elsevier Inc. All rights reserved.