NMDA receptors inhibit synapse unsilencing during brain development
NMDA receptors inhibit synapse unsilencing during brain development
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DOI：
10.1073/pnas.0800946105
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发表时间：
2008-04-08
影响因子：
11.1
通讯作者：
Nicoll, Roger A.
中科院分区：
文献类型：
--
作者：
Adesnik, Hillel;Li, Guangnan;Nicoll, Roger A.
如何准确地确定成年哺乳动物大脑中的数十亿个突触，仍然是神经科学的基本问题之一。尽管遗传程序很可能编码基本的神经蓝图，但许多证据表明，通过NMDA受体的经验驱动活动通过诱导类似于长期增强的过程来连接神经元电路。为了直接测试这一概念，我们在体外和体内的单细胞突触发生之前和期间消除了NMDA受体。虽然流行的模型预测NMDA受体缺失应强烈抑制兴奋回路的成熟，但我们发现，NMDA受体功能的遗传消融显著增加了神经元之间功能性突触的数量。相反，将NMDA受体重新引入NR1缺乏的神经元，减少了功能输入的数量，这一过程需要网络活动和NMDA受体功能。虽然NMDA受体缺失增加了单一连接的强度，但并不改变神经元的形态，这表明基础的NMDA受体激活阻止了AMPA受体向沉默突触的募集。基于这些结果，我们提出了一种兴奋性突触成熟的新模型，在该模型中，NMDA受体的持续激活通过确保只有间断的活动突发才能诱导功能性突触，从而防止突触过早成熟，从而实现神经回路的活性依赖连接。
How the billions of synapses in the adult mammalian brain are precisely specified remains one of the fundamental questions of neuroscience. Although a genetic program is likely to encode the basic neural blueprint, much evidence suggests that experience-driven activity through NMDA receptors wires up neuronal circuits by inducing a process similar to long-term potentiation. To test this notion directly, we eliminated NMDA receptors before and during synaptogenesis in single cells in vitro and in vivo. Although the prevailing model would predict that NMDA receptor deletion should strongly inhibit the maturation of excitatory circuits, we find that genetic ablation of NMDA receptor function profoundly increases the number of functional synapses between neurons. Conversely, reintroduction of NMDA receptors into NR1-deficient neurons reduces the number of functional inputs, a process requiring network activity and NMDA receptor function. Although NMDA receptor deletion increases the strength of unitary connections, it does not alter neuronal morphology, suggesting that basal NMDA receptor activation blocks the recruitment of AMPA receptors to silent synapses. Based on these results we suggest a new model for the maturation of excitatory synapses in which ongoing activation of NMDA receptors prevents premature synaptic maturation by ensuring that only punctuated bursts of activity lead to the induction of a functional synapse for the activity-dependent wiring of neural circuitry.