Integrated Program in Neuroscience, McGill University, Montréal, Québec, Canada H3A 2B4.
Department of Pharmacology and Therapeutics, McGill University, Montréal H3G 0B1, Québec, Canada.
J Neurosci. 2020 Apr 22;40(17):3348-3359. doi: 10.1523/JNEUROSCI.2211-19.2020. Epub 2020 Mar 13.
Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABA receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABARs synapses through a GΑΒΑ receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway. Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABA receptor synapses via Ca/calmodulin-dependent protein kinase II. Although Ca transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.
一氧化氮（NO）是一种重要的信号分子，作为神经递质或可扩散的第二信使，在中枢神经系统（CNS）的发育和成熟过程中发挥着多样化的功能作用。尽管 NO 对不同行为（如运动、睡眠、学习和记忆）的影响已得到充分证实，但它的分子和细胞靶标仍然是一个正在研究的领域。在这里，我们发现了一种新的作用机制，即 NO 可增强小脑分子层中间神经元中 GABA 受体介导的抑制性传递。NO 水平可通过神经元型一氧化氮合酶（nNOS）在细胞外突触 NMDA 型离子型谷氨酸受体（NMDAR）通过 Ca 内流后升高。NO 通过随后产生 cGMP 激活蛋白激酶 G，从而刺激 NADPH 氧化酶和蛋白激酶 C（PKC）的产生。PKC 的激活通过 GΑΒΑ 受体相关蛋白依赖的机制促进选择性增强含有 α3 的 GABAR 突触。鉴于哺乳动物大脑中 NMDA 受体/nNOS 复合物的广泛但细胞类型特异性表达，我们的数据表明，NMDA 受体可能通过一种新型的 NO 介导途径，在这些细胞中特异性增强抑制性 GABA 能传递。GABA 能传递效率的长期变化是由多种突触前和突触后机制介导的。一个突出的途径是兴奋性和抑制性突触之间的串扰，其中通过突触后 NMDAR 进入的 Ca 促进通过 Ca/钙调蛋白依赖性蛋白激酶 II 募集和增强 GABA 受体突触。尽管 NMDAR 转运的 Ca 也与 nNOS 活性和 NO 产生紧密偶联，但尚不清楚该途径是否影响抑制性突触。在这里，我们表明 NMDAR 的激活触发了一种依赖于 NO 的途径，该途径可增强小脑分子层中间神经元的抑制性 GABA 能突触。鉴于哺乳动物大脑中 NMDA 受体和 nNOS 的广泛表达，我们推测 NO 对 GABA 能突触效能的控制可能比以前认为的更为广泛。
