Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo.
Abnormal intrinsic dynamics of dendritic spines in a fragile X syndrome mouse model in vivo.
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DOI：
10.1038/srep26651
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发表时间：
2016-05-25
影响因子：
4.6
通讯作者：
Kasai H
中科院分区：
文献类型：
--
作者：
Nagaoka A;Takehara H;Hayashi-Takagi A;Noguchi J;Ishii K;Shirai F;Yagishita S;Akagi T;Ichiki T;Kasai H
树突棘的产生和消除在学习和记忆中起着重要的作用，其动力学已经在体内的新皮质中得到了研究。在缺乏特定学习任务的情况下，也可以检测到脊柱翻转，在自闭症谱系障碍(ASD)的动物模型中，脊柱翻转经常被夸大。本研究旨在检验脊柱翻转的基线比率是否与活动有关。这是通过使用微流控脑界面和开放硬脑膜手术实现的，目的是取消野生型小鼠和脆性X综合征啮齿动物模型(Fmr1基因敲除[KO])视皮层中的神经元钙信号。在野生型和Fmr1KO小鼠中，发现大多数基线周转是活动无关的。因此，应用基质金属蛋白酶-9抑制剂选择性地恢复了在Fmr1 KO小鼠中观察到的异常脊柱动力学，而不影响野生型小鼠脊柱翻转的内在动力学。这些发现表明，树突棘的基线周转是由活动无关的内在动力学调节的。此外，这些结果表明，靶向异常的内在动力可能为ASD提供了一种新的治疗方法。
Dendritic spine generation and elimination play an important role in learning and memory, the dynamics of which have been examined within the neocortex in vivo. Spine turnover has also been detected in the absence of specific learning tasks, and is frequently exaggerated in animal models of autistic spectrum disorder (ASD). The present study aimed to examine whether the baseline rate of spine turnover was activity-dependent. This was achieved using a microfluidic brain interface and open-dura surgery, with the goal of abolishing neuronal Ca2+ signaling in the visual cortex of wild-type mice and rodent models of fragile X syndrome (Fmr1 knockout [KO]). In wild-type and Fmr1 KO mice, the majority of baseline turnover was found to be activity-independent. Accordingly, the application of matrix metalloproteinase-9 inhibitors selectively restored the abnormal spine dynamics observed in Fmr1 KO mice, without affecting the intrinsic dynamics of spine turnover in wild-type mice. Such findings indicate that the baseline turnover of dendritic spines is mediated by activity-independent intrinsic dynamics. Furthermore, these results suggest that the targeting of abnormal intrinsic dynamics might pose a novel therapy for ASD.