Inhibition of GluN2B-containing NMDA receptors in early life combined with social stress in adulthood leads to alterations in prefrontal PNNs in mice.

Q3 Medicine
生理学报 Pub Date : 2024-02-25
Yi-Rui Liang, Xue-Han Zhang
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引用次数: 0

Abstract

Perineuronal nets (PNNs) are specialized extracellular matrix (ECM) structures present in the central nervous system (CNS) and have been identified as significant regulators of developmental plasticity in the developing cortex. PNNs are particularly enriched in the cortex surrounding parvalbumin-expressing (PV+) cells. A growing body of evidence suggests that the abnormalities in PV+ neurons and PNNs are associated with various neurological disorders, including schizophrenia, which is a neurodevelopmental defect disease. The N-methyl-D-aspartate receptor (NMDAR) selective antagonist is frequently employed to establish animal models of schizophrenia in laboratory settings. The crucial involvement of GluN2B-containing NMDARs in the development of CNS has been extensively established. However, the role of GluN2B in the pathophysiology of schizophrenia has yet to be thoroughly investigated. The present study inhibited GluN2B function through intraperitoneal infusion of the GluN2B selective antagonist ifenprodil into juvenile mice aged 3-4 weeks, followed by the administration of social stress when these mice reached 9 weeks of age. Then, immunofluorescence staining was employed to examine the changes in the PNNs and PV+ cells, an acoustic startle and prepulse inhibition test was used to detect activities of the PV+ cells, and Western blot was used to quantify the protein expression levels of GluN2A and GluN2B in the prefrontal cortex (PFC). The study revealed that in the PFC of mice subjected to GluN2B antagonist treatment in early life and social stress in adulthood, there was an increase in the number of PV+ cells wrapped by PNNs, and a decrease in the activation of PV+ cells during the prepulse inhibition test, which is an indicator of sensory gating functions, as well as changes in the protein expression levels of GluN2A and GluN2B, which resulted in an increase in the ratio of GluN2A to GluN2B. These aberrations in the mice are comparable to those observed in animal models and patients with schizophrenia. The findings suggest that even a transient hypofunction of GluN2B in early life poses a significant risk for the emergence of schizophrenia symptoms in adulthood.

早期抑制含 GluN2B 的 NMDA 受体加上成年后的社会压力会导致小鼠前额叶 PNN 的改变。
神经元周围网(PNN)是存在于中枢神经系统(CNS)中的特化细胞外基质(ECM)结构,已被确定为发育中皮层发育可塑性的重要调节因子。PNNs在皮层中尤其富集于副发光素表达(PV+)细胞周围。越来越多的证据表明,PV+神经元和PNNs的异常与各种神经系统疾病有关,包括精神分裂症这种神经发育缺陷疾病。在实验室环境中,N-甲基-D-天冬氨酸受体(NMDAR)选择性拮抗剂经常被用来建立精神分裂症的动物模型。含 GluN2B 的 NMDAR 在中枢神经系统发育中的关键作用已被广泛证实。然而,GluN2B 在精神分裂症病理生理学中的作用仍有待深入研究。本研究通过向 3-4 周龄的幼鼠腹腔注射 GluN2B 选择性拮抗剂 ifenprodil 来抑制 GluN2B 的功能,然后在这些小鼠长到 9 周龄时给予社会应激。然后,采用免疫荧光染色法检测PNNs和PV+细胞的变化,采用声学惊吓和前脉冲抑制试验检测PV+细胞的活性,采用Western印迹法定量检测前额叶皮层(PFC)中GluN2A和GluN2B的蛋白表达水平。研究发现,在早期接受GluN2B拮抗剂治疗和成年后遭受社会压力的小鼠前额叶皮层中,被PNN包裹的PV+细胞数量增加,在作为感觉门控功能指标的前脉冲抑制试验中PV+细胞的激活减少,GluN2A和GluN2B的蛋白表达水平也发生了变化,导致GluN2A与GluN2B的比例增加。小鼠的这些畸变与在动物模型和精神分裂症患者身上观察到的畸变相当。研究结果表明,即使在生命早期出现短暂的 GluN2B 功能减退,也会对成年后精神分裂症状的出现构成重大风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
生理学报
生理学报 Medicine-Medicine (all)
CiteScore
1.20
自引率
0.00%
发文量
4820
期刊介绍: Acta Physiologica Sinica (APS) is sponsored by the Chinese Association for Physiological Sciences and Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences (CAS), and is published bimonthly by the Science Press, China. APS publishes original research articles in the field of physiology as well as research contributions from other biomedical disciplines and proceedings of conferences and symposia of physiological sciences. Besides “Original Research Articles”, the journal also provides columns as “Brief Review”, “Rapid Communication”, “Experimental Technique”, and “Letter to the Editor”. Articles are published in either Chinese or English according to authors’ submission.
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