Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models.
Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models.
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DOI：
10.3389/fnsyn.2010.00004
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发表时间：
2010
影响因子：
3.7
通讯作者：
Broadie K
中科院分区：
文献类型：
--
作者：
Gatto CL;Broadie K
正常的大脑功能需要在神经回路组装过程中兴奋性和抑制性突触形成的严格平衡。通常塑造和维持这种平衡的基因突变会导致严重的功能障碍，导致神经发育障碍，包括自闭症，癫痫和Rett综合征。这样的突变可能导致突触连接的有缺陷的架构结构、突触的分子组装和/或功能性突触发生。受影响的基因通常直接编码突触成分，但也包括调节子，其间接介导突触蛋白的合成或组装。最好的例子是脆性X综合征（FXS），这是智力残疾和自闭症谱系障碍的主要遗传原因。FXS由mRNA结合FMRP的丧失引起，FMRP在活性依赖性突触发生和可塑性机制中调节突触转录本运输、稳定性和翻译。FXS的遗传模型表现出显著的兴奋性和抑制性突触失衡，与认知和社会互动行为受损相关。翻译控制下游，一些特定的突触蛋白调节兴奋性与抑制性突触发生，独立或组合，这些蛋白质的损失也与中断神经发育。目前的努力是确定级联事件连接转录，翻译和特定的突触蛋白在维持兴奋性与抑制性突触在神经回路形成过程中的作用。这一重点包括在功能性突触回路的完善过程中微调兴奋和抑制的机制，以及后来在整个生命中调节这种平衡的机制。强大的新的遗传模型的使用已经开始阐明一系列神经发育疾病状态的兴奋/抑制失衡的机制基础。
Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states.