Dopamine-Regulated MicroRNA MiR-181a Controls GluA2 Surface Expression in Hippocampal Neurons
Dopamine-Regulated MicroRNA MiR-181a Controls GluA2 Surface Expression in Hippocampal Neurons
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DOI：
10.1128/mcb.05896-11
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发表时间：
2012-02-01
影响因子：
5.3
通讯作者：
Schratt, Gerhard M.
中科院分区：
文献类型：
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作者：
Saba, Reuben;Stoerchel, Peter H.;Schratt, Gerhard M.
AMPA型谷氨酸受体（AMPA-R）在突触上的动态表达是突触可塑性的关键决定因素，包括对滥用药物的神经适应。最近，microRNAs（miRNAs）已成为突触可塑性的重要转录后调节因子，但它们是否靶向谷氨酸受体介导这种作用尚不清楚。在这里，我们使用微阵列筛选来鉴定调节突触可塑性的miRNA，该区域是形成药物寻求习惯的关键大脑区域。在中等多刺神经元突触处显示出稳健富集的miRNA之一是miR-181 a。使用生物信息学工具，我们检测到一个高度保守的miR-181 a结合位点内的mRNA编码的GluA 2亚基的AMPA-Rs。miR-181 a在原代神经元中的过表达和敲低表明该miRNA是GluA 2表达的负转录后调节因子。此外，miR-181 a过表达减少海马神经元中GluA 2表面表达、棘形成和微型兴奋性突触后电流（mEPSC）频率，表明miR-181 a可以调节突触功能。此外，在慢性药物治疗的小鼠模型中，原代神经元中的多巴胺信号传导以及可卡因和安非他明诱导了miR-181 a的表达。总之，我们的研究结果确定miR-181 a作为哺乳动物AMPA型谷氨酸受体的关键调节因子，对药物诱导的突触可塑性的调节具有潜在意义。
The dynamic expression of AMPA-type glutamate receptors (AMPA-R) at synapses is a key determinant of synaptic plasticity, including neuroadaptations to drugs of abuse. Recently, microRNAs (miRNAs) have emerged as important posttranscriptional regulators of synaptic plasticity, but whether they target glutamate receptors to mediate this effect is not known. Here we used microarray screening to identify miRNAs that regulate synaptic plasticity within the nucleus accumbens, a brain region critical to forming drug-seeking habits. One of the miRNAs that showed a robust enrichment at medium spiny neuron synapses was miR-181a. Using bioinformatics tools, we detected a highly conserved miR-181a binding site within the mRNA encoding the GluA2 subunit of AMPA-Rs. Overexpression and knockdown of miR-181a in primary neurons demonstrated that this miRNA is a negative posttranscriptional regulator of GluA2 expression. Additionally, miR-181a overexpression reduced GluA2 surface expression, spine formation, and miniature excitatory postsynaptic current (mEPSC) frequency in hippocampal neurons, suggesting that miR-181a could regulate synaptic function. Moreover, miR-181a expression was induced by dopamine signaling in primary neurons, as well as by cocaine and amphetamines, in a mouse model of chronic drug treatment. Taken together, our results identify miR-181a as a key regulator of mammalian AMPA-type glutamate receptors, with potential implications for the regulation of drug-induced synaptic plasticity.