Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression
Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression
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DOI：
10.1016/j.bbr.2018.10.011
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发表时间：
2019-02-01
影响因子：
2.7
通讯作者：
Adzic, Miroslav
中科院分区：
文献类型：
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作者：
Francija, Ester;Petrovic, Zorica;Adzic, Miroslav
最近的研究表明，脂多糖（LPS）诱导的抑郁样行为是通过NMDA受体介导的。在本研究中，我们进一步研究了NMDA受体GluN 2A亚基在LPS诱导的抑郁样行为中在前额叶皮层（PFC）和海马突触过程中的作用。我们的数据表明，LPS处理的小鼠，缺乏GluN 2 A亚基，没有表现出抑郁样行为。这是伴随着不变的IL-6水平和神经可塑性标志物和谷氨酸受体亚单位组成的PFC和海马的显着变化。特别地，GluN 2 A KO小鼠中的免疫攻击导致两种脑结构中的PSA-NCAM水平不变和proBDNF增加以及海马中BDNF水平增加。此外，GluN 2 A的缺乏导致LPS后PFC中所有NCAM亚型的水平增加，随后是GluN 1和GluN 2B亚基的减少。AMPA受体亚单位的水平这些结果表明GluN 2 A亚基在神经炎症相关的抑郁中是关键的，它的缺失消除了LPS诱导的抑郁表型，维持了PSA-NCAM水平，增加PFC和海马中的proBDNF信号传导，并在免疫攻击后通过PFC中的NCAM增强突触稳定性。
Recent reports have demonstrated that lipopolysaccharide (LPS)-induced depressive-like behaviour is mediated via NMDA receptor. In this study, we further investigated the role of GluN2 A subunit of NMDA receptor in synaptic processes in the prefrontal cortex (PFC) and hippocampus of GluN2 A knockout (KO) mice in LPS-induced depressive-like behavior. Our data suggest that LPS-treated mice, lacking GluN2 A subunit, did not exhibit depressive-like behaviour. This was accompanied by unaltered levels of IL-6 and significant changes in neuroplasticity markers and glutamate receptor subunits composition in PFC and hippocampus. In particular, an immune challenge in GluN2 A KO mice resulted in unchanged PSA-NCAM levels and proBDNF increase in both brain structures as well as in increase in BDNF levels in hippocampus. Furthermore, the absence of GluN2 A resulted in increased levels of all NCAM isoforms in PFC upon LPS which was followed with a decrease in GluN1 and GluN2B subunits. The levels of AMPA receptor subunits (GluA1, GluA3, and GluA4) in the hippocampus of GluN2 A mice were unaltered upon the treatment and abundantly present in the PFC of KO mice.These results indicate that the GluN2 A subunit is critical in neuroinflammation-related depression, that its absence abolishes LPS-induced depressive phenotype, sustains PSA-NCAM levels, increases proBDNF signalling in the PFC and hippocampus and potentiates synaptic stabilization through NCAM in the PFC upon an immune challenge.