Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
Nat Neurosci. 2012 Oct;15(10):1382-90. doi: 10.1038/nn.3214. Epub 2012 Sep 9.
NMDA receptors (NMDARs) are critical to synaptogenesis, neural circuitry and higher cognitive functions. A hallmark feature of NMDARs is an early postnatal developmental switch from those containing primarily GluN2B to primarily GluN2A subunits. Although the switch in phenotype has been an area of intense interest for two decades, the mechanisms that trigger it and the link between experience and the switch are unclear. Here we show a new role for the transcriptional repressor REST in the developmental switch of synaptic NMDARs. REST is activated at a critical window of time and acts via epigenetic remodeling to repress Grin2b expression and alter NMDAR properties at rat hippocampal synapses. Knockdown of REST in vivo prevented the decline in GluN2B and developmental switch in NMDARs. Maternal deprivation impaired REST activation and acquisition of the mature NMDAR phenotype. Thus, REST is essential for experience-dependent fine-tuning of genes involved in synaptic plasticity.
N-甲基-D-天冬氨酸受体（NMDARs）对于突触发生、神经回路和更高的认知功能至关重要。NMDAR 的一个显著特征是，在出生后的早期发育过程中，从主要含有 GluN2B 的受体转换为主要含有 GluN2A 的受体。尽管这种表型转换已经成为 20 年来的研究热点，但触发这种转换的机制以及经验与转换之间的联系尚不清楚。在这里，我们发现转录抑制因子 REST 在突触 NMDA 受体的发育性转换中具有新的作用。REST 在关键时间窗口被激活，并通过表观遗传重塑来抑制 Grin2b 的表达，改变大鼠海马突触上 NMDAR 的特性。体内敲低 REST 可防止 GluN2B 的减少和 NMDAR 受体的发育性转换。母体剥夺会损害 REST 的激活和成熟 NMDAR 表型的获得。因此，REST 对于涉及突触可塑性的基因的经验依赖性微调是必不可少的。
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