MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity.
MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity.
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DOI：
10.1038/ncomms10045
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发表时间：
2015-12-01
影响因子：
16.6
通讯作者：
Man HY
中科院分区：
文献类型：
--
作者：
Hou Q;Ruan H;Gilbert J;Wang G;Ma Q;Yao WD;Man HY
稳态突触可塑性是对神经元活动改变的补偿反应。神经元活动的慢性剥夺导致突触AMPA受体（AMPAR）和突触后电流的增加。GluA 2缺乏，钙可渗透的AMPAR（CP-AMPAR）的生物起源在稳态反应中起着至关重要的作用，然而，导致CP-AMPAR形成的机制仍不清楚。在这里，我们表明microRNA，miR 124，是产生CP-AMPAR和稳态可塑性所必需的。miR 124通过靶向GluA 2的3′-UTR抑制GluA 2的表达，导致CP-AMPAR的形成。阻断miR 124功能可消除稳态反应，而miR 124过表达可导致稳态可塑性的早期诱导。miR 124的转录受抑制性转录因子EVI 1控制，EVI 1通过与脱乙酰酶HDAC 1结合起作用。我们的数据支持一种细胞级联反应，其中失活解除了EVI 1/HDAC介导的对miR 124基因转录的抑制，导致miR 124表达增强，CP-AMPAR形成，随后诱导稳态突触可塑性。 已知缺乏GluA 2的AMPA受体在稳态可塑性中起作用。在这里，作者表明，尖峰活动阻断抑制mir 124转录，这反过来又抑制GluA 2 mRNA翻译，从而有助于海马细胞中的突触放大。
Homeostatic synaptic plasticity is a compensatory response to alterations in neuronal activity. Chronic deprivation of neuronal activity results in an increase in synaptic AMPA receptors (AMPARs) and postsynaptic currents. The biogenesis of GluA2-lacking, calcium-permeable AMPARs (CP-AMPARs) plays a crucial role in the homeostatic response; however, the mechanisms leading to CP-AMPAR formation remain unclear. Here we show that the microRNA, miR124, is required for the generation of CP-AMPARs and homeostatic plasticity. miR124 suppresses GluA2 expression via targeting its 3′-UTR, leading to the formation of CP-AMPARs. Blockade of miR124 function abolishes the homeostatic response, whereas miR124 overexpression leads to earlier induction of homeostatic plasticity. miR124 transcription is controlled by an inhibitory transcription factor EVI1, acting by association with the deacetylase HDAC1. Our data support a cellular cascade in which inactivity relieves EVI1/HDAC-mediated inhibition of miR124 gene transcription, resulting in enhanced miR124 expression, formation of CP-AMPARs and subsequent induction of homeostatic synaptic plasticity. GluA2-lacking AMPA receptors are known to play a role in homeostatic plasticity. Here, the authors show that spiking activity blockade disinhibits mir124 transcription, which in turn suppresses GluA2 mRNA translation, thereby contributing to synaptic upscaling in hippocampal cells.