Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1
Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1
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DOI：
10.1523/jneurosci.4315-14.2015
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发表时间：
2015-09-16
影响因子：
5.3
通讯作者：
Morishita, Hirofumi
中科院分区：
文献类型：
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作者：
Bukhari, Noreen;Burman, Poromendro N.;Morishita, Hirofumi
经验依赖性皮层可塑性随年龄增长而下降。在分子水平上，如果小鼠在标准笼中饲养，则组织纤溶酶原激活物（tPA）的经验依赖性蛋白水解活性在成年大脑中受到限制。因此，了解允许蛋白水解活性丧失的机制是改善成人大脑功能的关键环节。使用小鼠初级视觉皮层（V1）作为模型，我们证明，tPA活性V1可以被揭露后4天的单眼剥夺时，年龄大于2个月的小鼠提出了在标准笼中的遗传删除Lynx 1，成人可塑性的负调节。这也与Lynx 1基因敲除（KO）小鼠成年V1期的棘突和薄棘密度的减少以及眼优势移位的增强有关。这些结构和功能的变化是tPA依赖性的，因为在Lynx 1 KO小鼠中遗传去除tPA可以阻断单眼剥夺依赖性树突棘密度降低，而遗传和成人特异性抑制tPA活性可以消除Lynx 1 KO小鼠的眼优势转移。我们的工作表明，成年人的大脑有一个内在的潜力，经验依赖性的蛋白水解活性的升高，表达少年样的结构和功能的变化，但有效地限制了Lynx 1，如果小鼠在标准的笼子里。对Lynx 1-tPA可塑性机制的深入了解可能会为成人脑部疾病提供新的治疗靶点。
Experience-dependent cortical plasticity declines with age. At the molecular level, experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain if mice are raised in standard cages. Understanding the mechanism for the loss of permissive proteolytic activity is therefore a key link for improving function in adult brains. Using the mouse primary visual cortex (V1) as a model, we demonstrate that tPA activity in V1 can be unmasked following 4 d of monocular deprivation when the mice older than 2 months are raised in standard cages by the genetic removal of Lynx1, a negative regulator of adult plasticity. This was also associated with the reduction of stubby and thin spine density and enhancement of ocular dominance shift in adult V1 of Lynx1 knock-out ( KO) mice. These structural and functional changes were tPA-dependent because genetic removal of tPA in Lynx1 KO mice can block the monocular deprivation-dependent reduction of dendritic spine density, whereas both genetic and adult specific inhibition of tPA activity can ablate the ocular dominance shift in Lynx1 KO mice. Our work demonstrates that the adult brain has an intrinsic potential for experience-dependent elevation of proteolytic activity to express juvenile-like structural and functional changes but is effectively limited by Lynx1 if mice are raised in standard cages. Insights into the Lynx1-tPA plasticity mechanism may provide novel therapeutic targets for adult brain disorders.