Tulane University Neuroscience Program, 2013 Percival Stern Hall, 6400 Freret Street, New Orleans, LA 70118, USA.
Neuron. 2011 Dec 8;72(5):789-805. doi: 10.1016/j.neuron.2011.09.023.
The subunit composition of N-methyl D-aspartate receptors (NMDARs) is tightly regulated during cortical development. NMDARs are initially dominated by GluN2B (NR2B), whereas GluN2A (NR2A) incorporation increases after birth. The function of GluN2B-containing NMDARs during development, however, is incompletely understood. We generated a mouse in which we genetically replaced GluN2B with GluN2A (2B→2A). Although this manipulation restored NMDAR-mediated currents at glutamatergic synapses, it did not rescue GluN2B loss of function. Protein translation-dependent homeostatic synaptic plasticity is occluded in the absence of GluN2B, and AMPA receptor contribution is enriched at excitatory cortical synapses. Our experiments indicate that specificity of GluN2B-mediated signaling is due to its unique interaction with the protein effector alpha calcium-calmodulin kinase II and the regulation of the mTOR pathway. Homozygous 2B→2A mice exhibited high rates of lethality, suppressed feeding, and depressed social exploratory behavior. These experiments indicate that GluN2B-containing NMDARs activate unique cellular processes that cannot be rescued by replacement with GluN2A.
N-甲基-D-天冬氨酸受体（NMDARs）的亚基组成在皮质发育过程中受到严格调控。NMDARs 最初主要由 GluN2B（NR2B）组成，而 GluN2A（NR2A）的掺入则在出生后增加。然而，GluN2B 包含的 NMDAR 在发育过程中的功能尚未完全理解。我们生成了一种小鼠，在这种小鼠中，我们通过基因手段将 GluN2B 替换为 GluN2A（2B→2A）。尽管这种操作恢复了谷氨酸能突触处的 NMDAR 介导的电流，但它并没有挽救 GluN2B 功能丧失。在缺乏 GluN2B 的情况下，蛋白翻译依赖性的同型突触可塑性被阻断，而 AMPA 受体的贡献在兴奋性皮质突触中得到富集。我们的实验表明，GluN2B 介导的信号传递的特异性是由于其与蛋白效应物α钙调蛋白激酶 II 的独特相互作用以及 mTOR 通路的调节。纯合的 2B→2A 小鼠表现出高死亡率、进食抑制和社交探索行为减少。这些实验表明，GluN2B 包含的 NMDAR 激活了独特的细胞过程，这些过程不能通过用 GluN2A 替换来挽救。
