Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.
Department of Neuroscience, Imaging, and Clinical Sciences (DNISC), University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.
Cells. 2022 Mar 7;11(5):911. doi: 10.3390/cells11050911.
Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons (also known as nNOS (+) neurons) are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a critical divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we indicate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.
兴奋性毒性是一种神经元死亡形式，其特征是兴奋性神经递质谷氨酸引发的 N-甲基-D-天冬氨酸受体（NMDAR）的持续激活。NADPH-黄递酶神经元（也称为 nNOS(+)神经元）是无棘突中间神经元的一个亚群，在兴奋性毒性挑战后基本得以幸免。与 nNOS(-)细胞不同，nNOS(+)神经元在 NMDAR 激活时无法产生活性氧物种，这是兴奋性级联反应中的一个关键分歧步骤。然而，尚未探索 nNOS(+)神经元对 NMDAR 驱动的神经元死亡的脆弱性降低的其他机制。我们使用纹状体培养物中的功能、遗传和分子分析表明，nNOS(+)神经元具有独特的 NMDAR 特性。这些特定特征主要由该亚群特殊的氧化还原环境驱动。此外，我们发现暴露于一种旨在模拟慢性兴奋性毒性的药理学操作的 nNOS(+)神经元改变了它们对 NMDAR 介导的挑战的反应。这些发现表明存在提供 NMDAR 长期动态调节的机制，这在神经毒性环境中可能具有重要意义。
