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幼年期抑制NMDA受体GluN2B亚基功能结合成年后社交应激改变小鼠前额叶皮层神经元周围网络

梁亦睿, 张雪寒^*

复旦大学脑科学研究院，医学神经生物学国家重点实验室，教育部脑科学前沿中心，上海 200032

摘要

神经元周围网络(perineuronal nets, PNNs)是一种细胞外基质(extracellular matrix, ECM)，被认为是神经系统发育，尤其是皮层发育过程中重要的神经可塑性调节因子。大脑皮层中的PNNs富集在表达小清蛋白(parvalbumin, PV)的中间神经元周围。越来越多的证据表明，PV阳性神经元和PNNs的异常与多种精神疾病相关，特别是属于发育缺陷疾病的精神分裂症。NMDA受体在精神分裂症的病理生理学中发挥重要作用，NMDA受体的选择性拮抗剂常用于精神分裂症实验模型动物的造模。GluN2B亚基在神经系统发育中发挥至关重要的作用，但GluN2B在精神分裂症中的作用尚缺乏研究。本研究通过腹腔注射GluN2B选择性拮抗剂ifenprodil干扰幼年小鼠(3~4周龄)的GluN2B亚基功能，待小鼠长至成年(9周龄)时，给予小鼠社会应激。用免疫荧光染色方法研究前额叶皮层(prefrontal cortex, PFC) PNNs和PV阳性神经元的变化，用听觉惊吓和前脉冲抑制测试检测PV阳性细胞活性，用免疫印迹技术检测NMDA受体GluN2A和GluN2B亚基蛋白的表达。结果显示，在幼年期GluN2B拮抗剂注射和成年应激处理的小鼠PFC中有更多的PV阳性神经元被PNNs包裹；在需要感觉门控功能支持的前脉冲抑制测试中被激活的PV阳性神经元显著减少；NMDA受体GluN2A/GluN2B亚基蛋白表达比例显著降低。小鼠的这些由幼年期GluN2B拮抗剂注射和成年应激引起的异常，与精神分裂症患者和动物模型中观察到的现象相似。以上研究结果提示幼年GluN2B功能异常，甚至短暂的功能低下，可能是成年后出现精神分裂症症状的风险因素之一。

关键词： NMDA受体; PV阳性中间神经元; 神经发育; 精神分裂症; 前额叶皮层; 啮齿类动物

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

LIANG Yi-Rui, ZHANG Xue-Han^*

State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China

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.

Key words: NMDA receptor; PV-positive interneuron; neurodevelopment; schizophrenia; prefrontal cortex; rodent

收稿日期：　　录用日期：

通讯作者：张雪寒　　E-mail: xuehanzhang@fudan.edu.cn

DOI: 10.13294/j.aps.2023.0056

引用本文：

梁亦睿, 张雪寒. 幼年期抑制NMDA受体GluN2B亚基功能结合成年后社交应激改变小鼠前额叶皮层神经元周围网络[J]. 生理学报 2024; 76 (1): 1-11.

LIANG Yi-Rui, ZHANG Xue-Han. Inhibition of GluN2B-containing NMDA receptors in early life combined with social stress in adulthood leads to alterations in prefrontal PNNs in mice. Acta Physiol Sin 2024; 76 (1): 1-11