Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models.
Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models.
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DOI：
10.3389/fncel.2014.00030
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发表时间：
2014
影响因子：
5.3
通讯作者：
Broadie K
中科院分区：
文献类型：
--
作者：
Doll CA;Broadie K
在回路特定的关键时期，早期使用活动通过消除不适当的突触和加强维持的突触的耦合过程来改善脑回路。我们推测这些活动依赖性（A-D）发育过程在自闭症谱系障碍（ASD）中特别受损。小鼠和果蝇中的ASD遗传模型开创了我们对正常A-D神经回路组装和巩固的见解，以及这些发育机制在特定遗传条件下如何出错。单基因脆性X综合征（FXS）是遗传性ASD和智力残疾的常见原因，与A-D关键期过程中的缺陷特别相关。脆性X智力低下蛋白（FMRP）的表达和功能是积极的活性调节，反过来又调节兴奋性和负反馈回路中的活动，并似乎是需要在早期使用的关键时期突触连接的A-D重塑。果蝇FXS模型已被证明在功能上保留了人类FMRP在突触发生中的作用，并且在产生我们目前对FXS疾病状态的机制理解方面具有重要意义。果蝇光遗传学、转基因钙报告基因、个体识别神经元的高度靶向转基因驱动程序以及大大改进的大脑连接体的最新进展现在正在结合起来，为在定义的神经回路中的关键时期大脑发育期间操纵和监测A-D过程提供无与伦比的机会。该领域现在准备利用这种新的果蝇转基因工具箱，系统地解剖正常与ASD大脑发育中的A-D机制，特别是利用成熟的果蝇FXS疾病模型。
Early-use activity during circuit-specific critical periods refines brain circuitry by the coupled processes of eliminating inappropriate synapses and strengthening maintained synapses. We theorize these activity-dependent (A-D) developmental processes are specifically impaired in autism spectrum disorders (ASDs). ASD genetic models in both mouse and Drosophila have pioneered our insights into normal A-D neural circuit assembly and consolidation, and how these developmental mechanisms go awry in specific genetic conditions. The monogenic fragile X syndrome (FXS), a common cause of heritable ASD and intellectual disability, has been particularly well linked to defects in A-D critical period processes. The fragile X mental retardation protein (FMRP) is positively activity-regulated in expression and function, in turn regulates excitability and activity in a negative feedback loop, and appears to be required for the A-D remodeling of synaptic connectivity during early-use critical periods. The Drosophila FXS model has been shown to functionally conserve the roles of human FMRP in synaptogenesis, and has been centrally important in generating our current mechanistic understanding of the FXS disease state. Recent advances in Drosophila optogenetics, transgenic calcium reporters, highly-targeted transgenic drivers for individually-identified neurons, and a vastly improved connectome of the brain are now being combined to provide unparalleled opportunities to both manipulate and monitor A-D processes during critical period brain development in defined neural circuits. The field is now poised to exploit this new Drosophila transgenic toolbox for the systematic dissection of A-D mechanisms in normal versus ASD brain development, particularly utilizing the well-established Drosophila FXS disease model.
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