MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction
MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction
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DOI：
10.1073/pnas.0805854106
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发表时间：
2009-03-03
影响因子：
11.1
通讯作者：
Wahlestedt, Claes
中科院分区：
文献类型：
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作者：
Kocerha, Jannet;Faghihi, Mohammad Ali;Wahlestedt, Claes
N-甲基-D-天冬氨酸（NMDA）谷氨酸受体是大脑中快速神经传递和突触可塑性的调节剂。NMDA介导的谷氨酸信号传导的中断与精神疾病如精神分裂症中显示的行为缺陷有关。最近，非编码RNA分子如microRNA（miRNAs）已成为神经元功能的关键调节因子。在这里，我们表明，药理学（地佐环平）或遗传（NR 1亚型）破坏NMDA受体信号转导降低了小鼠前额叶皮层（PFC）中脑特异性miRNA，miR-219的水平。与miR-219在NMDA受体信号传导中的作用一致，我们鉴定了钙/钙调蛋白依赖性蛋白激酶II γ亚基（CaMKII γ）（NMDA受体信号传导级联的一个组分）作为miR-219的靶点。在小鼠脑中通过特异性antimiR对miR-219的体内抑制显著调节与破坏NMDA受体传递相关的行为反应。此外，抗精神病药物氟哌啶醇和氯氮平预处理可预防地佐环平诱导的miR-219效应。总之，这些数据支持miR-219在与NMDA受体功能减退相关的行为畸变表达中的不可或缺的作用。
N-methyl-D-aspartate (NMDA) glutamate receptors are regulators of fast neurotransmission and synaptic plasticity in the brain. Disruption of NMDA-mediated glutamate signaling has been linked to behavioral deficits displayed in psychiatric disorders such as schizophrenia. Recently, noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators of neuronal functions. Here we show that pharmacological (dizocilpine) or genetic (NR1 hypomorphism) disruption of NMDA receptor signaling reduces levels of a brain-specific miRNA, miR-219, in the prefrontal cortex (PFC) of mice. Consistent with a role for miR-219 in NMDA receptor signaling, we identify calcium/calmodulin-dependent protein kinase II gamma subunit (CaMKII gamma), a component of the NMDA receptor signaling cascade, as a target of miR-219. In vivo inhibition of miR-219 by specific antimiR in the murine brain significantly modulated behavioral responses associated with disrupted NMDA receptor transmission. Furthermore, pretreatment with the antipsychotic drugs haloperidol and clozapine prevented dizocilpine-induced effects on miR-219. Taken together, these data support an integral role for miR-219 in the expression of behavioral aberrations associated with NMDA receptor hypofunction.