Adesnik Hillel, Li Guangnan, During Matthew J, Pleasure Samuel J, Nicoll Roger A
Departments of Cellular and Molecular Pharmacology, Physiology, and Neurology, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5597-602. doi: 10.1073/pnas.0800946105. Epub 2008 Mar 28.
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.
成年哺乳动物大脑中数十亿个突触是如何精确确定的，仍然是神经科学的基本问题之一。尽管遗传程序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时程增强的过程来连接神经元回路。为了直接验证这一概念，我们在体外和体内的单细胞突触形成之前和期间消除了NMDA受体。尽管普遍的模型预测NMDA受体缺失应强烈抑制兴奋性回路的成熟，但我们发现NMDA受体功能的基因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缺陷神经元会减少功能性输入的数量，这一过程需要网络活动和NMDA受体功能。尽管NMDA受体缺失增加了单一连接的强度，但它不会改变神经元形态，这表明基础NMDA受体激活会阻止AMPA受体募集到沉默突触。基于这些结果，我们提出了一种兴奋性突触成熟的新模型，其中NMDA受体的持续激活通过确保只有间歇性的活动爆发才能诱导功能性突触以进行神经回路的活动依赖性连接，从而防止突触过早成熟。
