neuroligin 1

神经凝集素 1
  • 文章类型: English Abstract
    目的:评估顶叶皮质反复轻度创伤性脑损伤(rmTBI)对小鼠延髓神经元形态和突触可塑性的影响。
    方法:32只雄性ICR小鼠随机分为假手术组(n=8)和rmTBI组(n=24)。后一组中的小鼠受到自由落体对顶叶皮质的反复轻度冲击损伤。使用神经严重程度评分(NSS)评估存活的小鼠的神经功能缺损,扶正反射测试和强迫游泳测试,HE和Nissl染色观察延髓神经元细胞的病理变化。免疫印迹和免疫荧光染色检测神经凝集素1(NLG-1)和突触后密度蛋白95(PSD-95)在rmTBI存活或不存活小鼠延髓中的表达。
    结果:假手术组小鼠均无死亡,rmTBI组死亡率为41.67%。存活的rmTBI小鼠显示NSS显著降低,扶正反射的延迟恢复,强迫游泳试验不动时间增加(P<0.05),和Nissl体的丢失;在延髓中的大量神经元中观察到肿胀和坏死,其中NLG-1和PSD-95的表达水平显著下调(P<0.05)。与未存活的小鼠相比,未存活的小鼠表现出神经纤维扭曲和肿胀,延髓中神经元密度降低,NLG-1和PSD-95的表达水平降低(P<0.01)。
    结论:延髓突触的结构和功能异常可能导致小鼠rmTBI后的死亡和神经功能缺损。
    OBJECTIVE: To assess the effects of repeated mild traumatic brain injury (rmTBI) in the parietal cortex on neuronal morphology and synaptic plasticity in the medulla oblongata of mice.
    METHODS: Thirty-two male ICR mice were randomly divided into sham operation group (n=8) and rmTBI group (n=24). The mice in the latter group were subjected to repeated mild impact injury of the parietal cortex by a free-falling object. The mice surviving the injuries were evaluated for neurological deficits using neurological severity scores (NSS), righting reflex test and forced swimming test, and pathological changes of the neuronal cells in the medulla oblongata were observed with HE and Nissl staining. Western blotting and immunofluorescence staining were used to detect the expressions of neuroligin 1(NLG-1) and postsynaptic density protein 95(PSD-95) in the medulla oblongata of the mice that either survived rmTBI or not.
    RESULTS: None of the mice in the sham-operated group died, while the mortality rate was 41.67% in rmTBI group. The mice surviving rmTBI showed significantly reduced NSS, delayed recovery of righting reflex, increased immobility time in forced swimming test (P < 0.05), and loss of Nissl bodies; swelling and necrosis were observed in a large number of neurons in the medulla oblongata, where the expression levels of NLG-1 and PSD-95 were significantly downregulated (P < 0.05). The mice that did not survive rmTBI showed distorted and swelling nerve fibers and decreased density of neurons in the medulla oblongina with lowered expression levels of NLG-1 and PSD-95 compared with the mice surviving the injuries (P < 0.01).
    CONCLUSIONS: The structural and functional anomalies of the synapses in the medulla oblongata may contribute to death and neurological impairment following rmTBI in mice.
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  • 文章类型: Journal Article
    背景:新生大鼠反复暴露七氟醚可能导致神经元凋亡,影响长期认知功能,机制未知。Neuroligin1(NL1)对于完整动物海马的正常兴奋性传递和长期突触可塑性至关重要。在这里,我们探讨NL1在新生大鼠海马兴奋性突触中对七氟烷反复暴露引起的长期认知障碍的作用。
    方法:从出生后第6天(P6)到P8天,新生大鼠每天暴露于30%氧气或3%七氟醚30%氧气2小时。每窝大鼠随机分为五组:对照组(Con),天然对照腺相关病毒(NC-AAV)组(Con+NC-AAV),七氟醚组(Sev),七氟醚+靶向NL1下调的重组RNAi腺相关病毒(NL1--AAV)组(Sev+NL1--AAV)和对照+靶向NL1上调的重组RNAi腺相关病毒(NL1+-AAV)组(Con+NL1+-AAV)。将NC-AAV或NL1-AAV注射到双侧海马CA1区并将其关在P21上。从P35到P40,包括开放场(OF)的行为测试,新颖的对象识别(NOR),进行了恐惧条件(FC)测试以评估青春期大鼠的认知功能。在另一个实验中,收集大鼠大脑进行免疫荧光染色,西方印迹,免疫共沉淀,和实时聚合酶链反应(PCR)。
    结果:我们发现Sev组NL1的mRNA和蛋白水平明显高于Con组。免疫荧光显示,反复七氟醚暴露后,NL1和PSD95在海马CA1区高度共定位,神经元周围的囊泡GABA转运蛋白(vGAT)减少。免疫共沉淀显示,与Con组相比,Sev组的PSD95与NL1抗体的量显著增加。这些大鼠在青少年时在NOR和FC测试中的表现比对照大鼠差。这些结果通过将NL1-AAV注射到CA1区域而被逆转。NL1+-AAV组与Sev组相似。
    结论:我们已经证明,新生儿七氟烷反复暴露会降低神经元周围的抑制性突触输入(用vGAT标记),这可能会影响海马兴奋性突触中NL1的上调,并增强NL1/PSD95的相互作用,最终导致青春期大鼠的长期认知障碍。注入NL1--AAV逆转了该损伤。这些结果表明,反复暴露于新生儿七氟醚后,兴奋性突触中的NL1有助于长期认知障碍。
    BACKGROUND: Repeated sevoflurane exposures in neonatal rats may lead to neuronal apoptosis affecting long-term cognitive function, the mechanism is unknown. Neuroligin1 (NL1) is essential for normal excitatory transmission and long-term synaptic plasticity in the hippocampus of intact animals. Herein, we explore the role of NL1 in hippocampal excitatory synapses on long-term cognitive impairments induced by repeated sevoflurane exposures in neonatal rats.
    METHODS: From postnatal day six (P6) to P8, neonatal rats were exposed to 30% oxygen or 3% sevoflurane +30% oxygen for 2 h daily. Rats from each litter were randomly assigned to five groups: control group (Con), native control adeno-associated virus (NC-AAV) group (Con + NC-AAV), sevoflurane group (Sev), sevoflurane + recombinant RNAi adeno-associated virus targeting NL1 downregulation (NL1--AAV) group (Sev + NL1--AAV) and control + recombinant RNAi adeno-associated virus targeting NL1 upregulation (NL1+-AAV) group (Con + NL1+-AAV). Animals were injected with NC-AAV or NL1-AAV into the bilateral hippocampal CA1 area and caged on P21. From P35 to P40, behavioral tests including open field (OF), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function in adolescent rats. In another experiment, rat brains were harvested for immunofluorescence staining, western blotting, co-immunoprecipitation, and real-time polymerase chain reaction (PCR).
    RESULTS: We found that the mRNA and protein levels of NL1 were substantially higher in the Sev group than in the Con group. Immunofluorescence showed that NL1 and PSD95 were highly colocalized in hippocampal CA1 area and vesicular GABA transporter (vGAT) around neurons decreased after repeated sevoflurane exposures. Co-immunoprecipitation showed that the amount of PSD95 with NL1 antibody was significantly increased in the Sev group compared to the Con group. These rats had a poorer performance in the NOR and FC tests than control rats when they were adolescents. These results were reversed by NL1--AAV injection into the CA1 area. NL1+-AAV group was similar to the Sev group.
    CONCLUSIONS: We have demonstrated that repeated neonatal sevoflurane exposures decreased inhibitory synaptic inputs (labelled by vGAT) around neurons, which may influence the upregulation of NL1 in hippocampal excitatory synapses and enhanced NL1/PSD95 interaction, ultimately leading to long-term cognitive impairments in adolescent rats. Injecting NL1--AAV reversed this damage. These results suggested that NL1 in excitatory synapses contributes to long-term cognitive impairments after repeated neonatal sevoflurane exposures.
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  • 文章类型: Journal Article
    OBJECTIVE: Postoperative cognitive dysfunction (POCD) is a common and significant syndrome. Our previous studies have shown that surgery reduces dendritic arborization and spine density and that environment enrichment (EE) reduces POCD. Neuroligin 1 is a postsynaptic protein involved in the formation of postsynaptic protein complex. This study was designed to determine the role of neuroligin 1 in the protection of EE against POCD and the mechanisms for EE to affect neuroligin 1 expression.
    METHODS: Eight-week-old C57BL/6J male mice with or without EE for 3, 7, or 14 days had right carotid artery exposure under isoflurane anesthesia. An anti-neuroligin 1 antibody at 1.5 µg/mouse was injected intracerebroventricularly at one and two weeks before the surgery. Mice were subjected to the Barnes maze and fear conditioning tests from one week after the surgery. Cerebral cortex and hippocampus were harvested after surgery.
    RESULTS: Mice with surgery had poorer performance in the Barnes maze and fear conditioning tests than control mice. EE for 2 weeks, but not EE for 3 or 7 days, improved the performance of surgery mice in these tests. Surgery reduced neuroligin 1 in the hippocampus. Preoperative EE for 2 weeks attenuated this reduction. The anti-neuroligin 1 antibody worsened the performance of mice with surgery plus EE in the Barnes maze and fear conditioning tests. Surgery increased histone deacetylase activity and decreased the acetylated histone in the hippocampus. EE attenuated these surgery effects.
    CONCLUSIONS: Our results suggest that preoperative EE for 2 weeks reduces POCD. This effect may be mediated by preserving neuroligin 1 expression via attenuating surgery-induced epigenetic dysregulation in the brain.
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  • 文章类型: Journal Article
    Perturbations to postsynaptic glutamate receptors (GluRs) trigger retrograde signaling to precisely increase presynaptic neurotransmitter release, maintaining stable levels of synaptic strength, a process referred to as homeostatic regulation. However, the structural change of homeostatic regulation remains poorly defined. At wild-type Drosophila neuromuscular junction synapse, there is one Bruchpilot (Brp) ring detected by superresolution microscopy at active zones (AZs). In the present study, we report multiple Brp rings (i.e., multiple T-bars seen by electron microscopy) at AZs of both male and female larvae when GluRs are reduced. At GluRIIC-deficient neuromuscular junctions, quantal size was reduced but quantal content was increased, indicative of homeostatic presynaptic potentiation. Consistently, multiple Brp rings at AZs were observed in the two classic synaptic homeostasis models (i.e., GluRIIA mutant and pharmacological blockade of GluRIIA activity). Furthermore, postsynaptic overexpression of the cell adhesion protein Neuroligin 1 partially rescued multiple Brp rings phenotype. Our study thus supports that the formation of multiple Brp rings at AZs might be a structural basis for synaptic homeostasis.SIGNIFICANCE STATEMENT Synaptic homeostasis is a conserved fundamental mechanism to maintain efficient neurotransmission of neural networks. Active zones (AZs) are characterized by an electron-dense cytomatrix, which is largely composed of Bruchpilot (Brp) at the Drosophila neuromuscular junction synapses. It is not clear how the structure of AZs changes during homeostatic regulation. To address this question, we examined the structure of AZs by superresolution microscopy and electron microscopy during homeostatic regulation. Our results reveal multiple Brp rings at AZs of glutamate receptor-deficient neuromuscular junction synapses compared with single Brp ring at AZs in wild type (WT). We further show that Neuroligin 1-mediated retrograde signaling regulates multiple Brp ring formation at glutamate receptor-deficient synapses. This study thus reveals a regulatory mechanism for synaptic homeostasis.
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  • 文章类型: Journal Article
    目的:Neurexin-1β和Neuroligin-1在其形成中起重要作用,维护,和调节突触结构。本研究旨在评估neurexin-1β和neuroligin-1在蛛网膜下腔出血(SAH)引起的认知功能障碍中的潜在作用。
    方法:体内,使用228只Sprague-Dawley大鼠。通过单次血液注射到前腔池来诱导实验性SAH模型。将原代培养的海马神经元暴露于氧合血红蛋白以在体外模拟SAH。在体内和体外都开发了针对nurexin-1β和neuroligin-1的特异性小干扰RNA和表达质粒。蛋白质印迹,免疫荧光,免疫沉淀,神经学评分,和Morris水迷宫进行评估,以评估Neurexin-1β和Neuroligin-1的机制以及神经系统的预后。
    结果:体内和体外实验均显示SAH诱导的神经元中neurexin-1β和neuroligin-1的表达减少,以及neurexin-1β和neuroligin-1之间的相互作用。此外,Neurexin-1β和Neuroligin-1之间的相互作用因它们的敲低而减少,并因它们的过表达而增加。通过氧合血红蛋白处理抑制兴奋性突触的形成,nurexin-1β和neuroligin-1的过表达显着改善,而nurexin-1β和neuroligin-1的敲低则加重。更重要的是,神经肽-1β和神经凝集素-1过表达改善SAH诱导的认知功能障碍,而neurexin-1β和neuroligin-1敲低诱导相反的作用。
    结论:增强Neurexin-1β和Neuroligin-1的表达可以促进它们之间的相互作用和兴奋性突触的形成。有助于改善SAH后认知功能障碍。Neurexin-1β和Neuroligin-1可能是改善SAH后认知功能的良好靶点。
    OBJECTIVE: Neurexin-1β and neuroligin-1 play an important role in the formation, maintenance, and regulation of synaptic structures. This study is to estimate the potential role of neurexin-1β and neuroligin-1 in subarachnoid hemorrhage (SAH)-induced cognitive dysfunction.
    METHODS: In vivo, 228 Sprague-Dawley rats were used. An experimental SAH model was induced by single blood injection to prechiasmatic cistern. Primary cultured hippocampal neurons were exposed to oxyhemoglobin to mimic SAH in vitro. Specific small interfering RNAs and expression plasmids for neurexin-1β and neuroligin-1 were exploited both in vivo and in vitro. Western blot, immunofluorescence, immunoprecipitation, neurological scoring, and Morris water maze were performed to evaluate the mechanism of neurexin-1β and neuroligin-1, as well as neurological outcome.
    RESULTS: Both in vivo and in vitro experiments showed SAH-induced decrease in the expressions of neurexin-1β and neuroligin-1 and the interaction between neurexin-1β and neuroligin-1 in neurons. In addition, the interaction between neurexin-1β and neuroligin-1 was reduced by their knockdown and increased by their overexpression. The formation of excitatory synapses was inhibited by oxyhemoglobin treatment, which was significantly ameliorated by overexpression of neurexin-1β and neuroligin-1 and aggravated by the knockdown of neurexin-1β and neuroligin-1. More importantly, neurexin-1β and neuroligin-1 overexpression ameliorated SAH-induced cognitive dysfunction, whereas neurexin-1β and neuroligin-1 knockdown induced an opposite effect.
    CONCLUSIONS: Enhancing the expressions of neurexin-1β and neuroligin-1 could promote the interaction between them and the formation of excitatory synapses, which is helpful to improve cognitive dysfunction after SAH. Neurexin-1β and neuroligin-1 might be good targets for improving cognitive function after SAH.
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