Age-related NMDA signaling alterations in SOD2 deficient mice
Age-related NMDA signaling alterations in SOD2 deficient mice
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DOI：
10.1016/j.bbadis.2018.03.019
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发表时间：
2018-06-01
影响因子：
6.2
通讯作者：
Cerpa, Waldo
中科院分区：
文献类型：
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作者：
Carvajal, Francisco J.;Mira, Rodrigo G.;Cerpa, Waldo
氧化应激影响神经元的存活和功能。因此，它们具有复杂且高度调节的机制来处理氧化变化。这种抗氧化机制的失调与广泛的神经退行性疾病有关。因此，我们评估了2个月和6个月大的杂合锰超氧化物歧化酶基因敲除小鼠（SOD 2（+/-）小鼠）的信号改变、突触特性和行为表现。我们发现它们的低抗氧化能力在蛋白质、脂质和DNA中产生直接的氧化损伤。然而，只有6个月大的杂合基因敲除小鼠表现出行为障碍。另一方面，突触可塑性，突触强度和NMDA受体（NMDAR）依赖的突触后电位下降，以年龄依赖的方式。我们还分析了NMDAR亚基G1 uN 2B的磷酸化状态。我们发现，虽然酪氨酸1472（突触形式）磷酸化的G1 uN 2B水平保持不变，我们检测到酪氨酸1336（突触外形式）磷酸化的G1 uN 2B水平增加，建立G1 uN 2B的突触/突触外比率的改变。此外，我们发现与p-1472去磷酸化相关的两种磷酸酶水平增加：纹状体富集蛋白酪氨酸磷酸酶（STEP）和10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）。此外，我们发现p-CREB水平下降，这是一种由突触刺激激活的主转录因子。总之，我们描述了氧化应激条件下突触改变的机制。我们的研究结果揭示了新的假定治疗靶点的条件下，NMDAR下游信号被改变。这项工作也有助于我们理解神经病理条件下的突触形成，学习和记忆等过程。
Oxidative stress affects the survival and function of neurons. Hence, they have a complex and highly regulated machinery to handle oxidative changes. The dysregulation of this antioxidant machinery is associated with a wide range of neurodegenerative conditions. Therefore, we evaluated signaling alterations, synaptic properties and behavioral performance in 2 and 6-month-old heterozygous manganese superoxide dismutase knockout mice (SOD2(+/-) mice). We found that their low antioxidant capacity generated direct oxidative damage in proteins, lipids, and DNA. However, only 6-month-old heterozygous knockout mice presented behavioral impairments. On the other hand, synaptic plasticity, synaptic strength and NMDA receptor (NMDAR) dependent postsynaptic potentials were decreased in an age-dependent manner. We also analyzed the phosphorylation state of the NMDAR subunit G1uN2B. We found that while the levels of G1uN2B phosphorylated on tyrosine 1472 (synaptic form) remain unchanged, we detected increased levels of G1uN2B phosphorylated on tyrosine 1336 (extrasynaptic form), establishing alterations in the synaptic/extrasynaptic ratio of G1uN2B. Additionally, we found increased levels of two phosphatases associated with dephosphorylation of p-1472: striatal-enriched protein tyrosine phosphatase (STEP) and phosphatase and tensin homolog deleted on chromosome Ten (PTEN). Moreover, we found decreased levels of p-CREB, a master transcription factor activated by synaptic stimulation. In summary, we describe mechanisms by which glutamatergic synapses are altered under oxidative stress conditions. Our results uncovered new putative therapeutic targets for conditions where NMDAR downstream signaling is altered. This work also contributes to our understanding of processes such as synapse formation, learning, and memory in neuropathological conditions.