幼鼠癫痫模型海马神经元NMDA受体表达与MMP-3表达相关性

目的 探讨幼鼠癫痫模型海马神经元N-甲基-D-天冬氨酸受体（NMDAR）表达与基质金属蛋白酶-3（MMP-3）表达的相关性。方法 将60只2~4周龄SPF级C57/BL6小鼠随机分为正常组、癫痫组、MMP-3抑制剂组、NMDAR抑制剂组,每组15只。采用匹罗卡品建立幼鼠癫痫模型;采用RT-PCR检测海马神经元NMDAR2A、NMDAR2B、MMP-3 mRNA表达;采用尼氏染色观察海马区神经元形态;采用Western blot检测海马区P-糖蛋白（P-gp）、钙调蛋白激酶Ⅱ（CAMKⅡ）蛋白表达。结果 幼鼠癫痫模型海马区NMDAR2A/B、MMP-3 mRNA以及P-gp、CAMKⅡ蛋白较正常组显著增加（P<0.05）。注射NMDA受体抑制剂或MMP-3抑制剂可显著降低幼鼠癫痫模型NMDAR2A/B、MMP-3 mRNA及P-gp、CAMKⅡ蛋白表达,且明显改善海马区神经元结构。结论 幼鼠癫痫模型海马神经元MMP-3表达与MNDAR表达可能具有相关性。     

The rtPA increases MMP-9 activity in serum during ischaemic stroke

Background and purposeTo find the relationship between rtPA treatment vs. MMP-9 activity, MMP-3, and TIMP-1 serum levels related to patients’ neurological status during acute ischaemic stroke (IS).Material and methods35 IS patients were enrolled. 14 of them underwent thrombolytic therapy with Actylise (rtPA group). The serum samples were obtained at 3 time-points for rtPA group (time-point 0: 1st–4th hour of stroke; time-point 1 – immediately after rtPA administration; time-point 2 – on day 5–7 from stroke onset). Remaining patients had venous blood collection at two time-points: time-point 1 – 5th–10th hour of stroke and time-point 2 – on day 5–7 of stroke. MMP-9 was analyzed with gelatin zymography, MMP-3 and TIMP-1 serum levels were analyzed with ELISA method. NIHSS improvement ratio (IR) was calculated as a difference between NIHSS score at the admission and discharge of patient.ResultsThe active form of MMP-9 (86 kDa) was not observed in any analyzed samples. Total MMP-9 activity was significantly elevated at time-point 1 in rtPA group in comparison with non-rtPA group. MMP-3 serum level significantly decreased during rtPA administration in comparison with non-rtPA group and it was restored at time-point 2. MMP-3 negatively correlated with IR values (p = 0.06).ConclusionsThrombolysis applied for IS treatment increases MMP-9 activity in serum, however, rtPA does not facilitate the conversion of pro-MMP-9 into the active form. Our results also suggest the involvement of MMP-3 to the biochemical processes occurring during acute phase of IS.     

Changes in the structure of synaptic junctions during climbing fiber synaptogenesis

Synaptogenesis between climbing fiber axons and Purkinje cells involves both an orderly translocation of synaptic junctions over the Purkinje cell surface and an elimination of all but one innervating axon. We used thin-section and freeze-fracture electron microscopic techniques to study structural changes in synaptic junctions during this interval of synapse translocation and elimination. In freeze-fractured preparations, virtually all climbing fiber synaptic junctions with the perisomatic processes and somatic spines lacked the particle aggregates that characterized the extracellular half of the postsynaptic membrane of mature synaptic junctions with dendritic spines. Some climbing fiber junctions with the dendritic shaft in the second postnatal week were associated with such aggregates, despite the fact that these junctions are transient. Thus, during the interval when Purkinje cells initially were innervated by multiple climbing fibers, and subsequently denervated of all but one climbing fiber afferent per cell, only a few of the transient synaptic junctions on the cell body and proximal dendrites have associated particles. The presence of a particle aggregate at a synaptic junction does not appear to be correlated with the permanence of that junction and probably is not correlated with the capacity to support synaptic transmission. The particle aggregates might be indicative of relatively long-lived junctions, or might occur only at junctions formed by the climbing fiber that will persist in synaptic contact with the mature Purkinje cell.     

N-cadherin在颞叶癫痫海马苔藓纤维出芽和突触重组中的作用

目的 探讨神经性钙粘附分子(N-cadherin)在癫痫状态后海马苔藓纤维出芽和突触重组中的作用。方法取锂一匹罗卡品诱导大鼠癫痫持续状态及慢性自发性颞叶癫痫发作期的大鼠脑片，用Timm染色和免疫组化的方法分别检测苔藓纤维出芽和N-cadherin在大鼠海马组织中的表达。结果癫痫状态后第2周和第4周的实验组大鼠可见到苔藓纤维出芽，穿越齿状回颗粒细胞层到达内分子层，并在此形成一条致密的层状带(Timm染色)。免疫组化染色发现实验组大鼠在第2周和第4周，海马齿状回内分子层可以看到强染色，并形成一条致密带，与Timm染色时观察到的条带一致。结论癫痫状态后在海马齿状回内分子层N-cadherin的表达上调．N-cadherin可能参与了癫痫后苔藓纤维出芽和突触重组过程。     

大鼠脑出血后脑组织MMP-2、MMP-9 表达的实验研究

目的　探讨大鼠脑出血后不同时程脑组织中的基质金属蛋白酶 - 2 ( MMP- 2 )、基质金属蛋白酶 - 9( MMP- 9)的表达及其规律。方法　采用立体定向技术制作大鼠脑出血模型 ,在脑出血后不同时间分别断头取脑 ,免疫组化法测定脑组织 MMP- 2、MMP- 9的表达量。结果　 ( 1)与假手术对照组比较 ,脑出血后 6 h血肿周围可见到微血管内皮表达 MMP- 9( P<0 .0 1) ,48h达高峰 ,至 5～ 7d后下降 ,但仍高于假手术对照组 ( P<0 .0 1) ,2周时降至零表达 ;12～ 2 4h中性粒细胞亦表达 MMP- 9;( 2 ) MMP- 2的表达要迟于 MMP- 9,2 4h可见到少量的 MMP- 2表达 ( P>0 .0 5 ) ,5～ 7d时逐渐达高峰 ( P<0 .0 1) ,主要在巨噬细胞上表达 ,2周时仍保持较高水平 ( P<0 .0 1)。结论　脑出血后出血侧血肿边缘有 MMP- 9、MMP- 2表达 ,推测 MMP- 9在急性期参与了脑水肿的形成 ,而 MMP- 2在脑出血后期可能参与了脑组织的修复.     

Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions

The pathology of multiple sclerosis (MS) is characterised by breakdown of the blood-brain barrier accompanied by infiltration of macrophages and T cells into the central nervous system (CNS). Myelin is degraded and engulfed by the macrophages, producing lesions of demyelination. Some or all of these mechanisms might involve proteinases, and here we have studied the cellular localisation and distribution of two matrix metalloproteinases (MMPs), MMP-7 (matrilysin) and MMP-9 (92-kDa gelatinase), in the normal human CNS and active demyelinating MS lesions. Cryostat sections of CNS samples were immunostained with antisera to MMP-7 and MMP-9. In addition, non-radioactive in situ hybridisation (ISH) was performed using a digoxygenin-labelled riboprobe to detect the expression of MMP-7. MMP-7 immunoreactivity was weakly detected in microglial-like cells in normal brain tissue sections, and was very strong in parenchymal macrophages in active demyelinating MS lesions. This pattern of expression was confirmed using ISH. MMP-7 immunoreactivity was not detected in macrophages in spleen or tonsil, indicating that it is specifically induced in infiltrating macrophages in active demyelinating MS lesions. MMP-9 immunoreactivity was detected in a few small blood vessels in normal brain tissue sections, whereas many blood vessels stained positive in CNS tissue sections of active demyelinating MS lesions. The up-regulation of MMPs in MS may contribute to the pathology of the disease. Received: 19 December 1996 / Revised: 22 May 1997 / Accepted: 4 June 1997     

MMP-2、MMP-9在人脑胶质瘤及其浸润组织中的表达和临床意义

目的 阐述MMP-2、MMP-9与胶质瘤的浸润机制.方法 应用免疫组化方法 和原位杂交方法 检测胶质瘤和胶质瘤浸润组织中的MMP-2、MMP-9蛋白及MMP-2 mRNA、MMP-9 mRNA的表达.结果 MMP-2 mRNA和MMP-9 mRNA表达在Ⅰ、Ⅱ、Ⅲ和Ⅳ级胶质瘤的阳性表达分别为5.26±1.47、9.51±0.96、14.58±1.42、20.56 4±1.56和7.90±0.50、14.46±0.75、23.54±1.32、28.07±0.81.MMP-2 mRNA和MMP-9 mRNA在Ⅰ～Ⅱ级胶质瘤浸润组织与Ⅲ～Ⅳ级胶质瘤浸润组织中的阳性表达分别为5.70±0.95、8.20±0.43和2.30±0.14、10.32±0.65.两者之间有显著差异(P<0.01).结论 胶质瘤的恶性程度与MMP-2、MMP-9表达呈正相关,随着胶质瘤的恶性程度的增高而增加.恶性程度高的胶质瘤,分泌基质金属蛋白酶能力越强,肿瘤的浸润性也越强.在胶质瘤治疗的过程中,即使肿瘤组织自身被切除,浸润组织则是胶质瘤复发的根源.     

ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory

Alzheimer's disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype.     

丁苯酞对脑缺血再灌注损伤大鼠MMP-9活性和血脑屏障通透性的影响

目的探讨丁苯酞对脑缺血再灌注损伤大鼠的保护作用。方法通过线栓法制备大鼠局灶性脑缺血再灌注损伤模型,腹腔注射丁苯酞,于脑缺血再灌注后6h、12h、24h后用免疫组织化学的方法观察损伤侧脑组织MMP-9活性及基底膜成分Ⅳ型(collagenⅣ)胶原表达的变化。同时测定伊文思兰的含量观察损伤侧脑组织血脑屏障通透性。结果随缺血再灌注时间延长,MMP-9活性、EB含量逐渐增加,24h达峰,Ⅳ型胶原的表达逐渐减少,各组之间表达均具有统计学意义(P<0.05);丁苯酞处理组MMP-9活性、EB含量各个时间点明显低于缺血再灌注组,相同时间点Ⅳ型胶原的表达增加(P<0.05)。结论丁苯酞可抑制脑缺血再灌注损伤大鼠MMP-9的表达,增加基底膜Ⅳ型胶原的表达,降低血脑屏障通透性,从而发挥脑保护作用。     

Clozapine and haloperidol differentially regulate dendritic spine formation and synaptogenesis in rat hippocampal neurons

Antipsychotic drugs are the primary therapeutic treatment for schizophrenia. In addition to their dopaminergic/serotonergic function, atypical antipsychotics differ from conventional antipsychotics in the way they affect glutamatergic receptor function. A cellular correlate of this may be the modulation of dendritic spines (DS). Here, we demonstrate that in rat dissociated hippocampal neurons 1.0 microM clozapine administration increased DS-enriched protein spinophilin by 70%, increased post-synaptic protein shank1a puncta density by 26% and increased overall primary dendrite DS density by 59%. Filopodia and mushroom DS were particularly affected by clozapine. Conversely, 0.1 microM haloperidol decreased spinophilin protein by 40%, caused a 25% decrease in shank1a puncta and reduced the numbers of filopodia. In contrast, neither haloperidol nor clozapine induced any change in the levels of the pre-synaptic protein synapsin. This indicates that clozapine and haloperidol differentially regulate DS and post-synaptic plasticity. These findings may provide a molecular and cellular correlate to the superior therapeutic profile of clozapine when compared with haloperidol.     

GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity

Hippocampal rhythms in clock gene expression, enzymatic activity, and long‐term potentiation (LTP) are thought to underlie day–night differences in memory acquisition and recall. Glycogen synthase kinase 3‐beta (GSK3β) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3β exhibits region‐specific differences over the light‐dark cycle. Here, we sought to determine whether phosphorylation of both GSK3α and GSK3β isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP). Results indicated a significant endogenous circadian rhythm in phosphorylation of GSK3β, but not GSK3α, in hippocampal CA1 extracts from mice housed in constant darkness for at least 2 weeks. To examine the importance of this rhythm, genetic and pharmacological strategies were used to disrupt the GSK3 activity rhythm by chronically activating or inhibiting GSK3. Chronic activation of both GSK3 isoforms in transgenic mice (GSK3‐KI mice) diminished rhythmic BMAL1 expression. On the other hand, chronic treatment with a GSK3 inhibitor significantly shortened the molecular clock period of organotypic hippocampal PER2::LUC cultures. While WT mice exhibited higher LTP magnitude at night compared to day, the day–night difference in LTP magnitude remained with greater magnitude at both times of day in mice with chronic GSK3 activity. On the other hand, pharmacological GSK3 inhibition impaired day–night differences in LTP by blocking LTP selectively at night. Taken together, these results support the model that circadian rhythmicity of hippocampal GSK3β activation state regulates day/night differences in molecular clock periodicity and a major form of synaptic plasticity (LTP).     

胶质瘤中MMP-2和TIMP-2的表达及意义

目的探讨MMP-2和TIMP-2与胶质瘤侵袭性及恶性表型之间的关系及其意义。方法采用Elivision二步免疫组织化学法染色观察MMP-2和TIMP-2在46例不同恶性度胶质瘤及10例正常脑组织中的表达并用德国LeicaQ550cw图像分析系统测其灰度值作为表达强度的量化指标。结果在对照组、低度及高度恶性胶质瘤中,MMP-2的阳性表达率分别为10%、63.6%和95.8%;在对照组、低度及高度恶性胶质瘤中,TIMP-2的阳性表达率分别为10%、36.3%和37.5%。MMP-2在Ⅰ、Ⅱ级和Ⅲ、Ⅳ级胶质瘤中平均灰度值分别为173.27±13.26和98.63±18.20;TIMP-2在Ⅰ、Ⅱ级和Ⅲ、Ⅳ级胶质瘤中平均灰度值分别为210.44±12.95和205.65±9.75。结论MMP-2表达随胶质瘤恶性程度增加而增强,可作为胶质瘤恶性表型及侵袭性指标之一。TIMP-2表达在正常脑组织及不同级别胶质瘤中无明显差异。MMP-2/TIMP-2的比值与胶质瘤侵袭性密切相关。     

Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits

Studies in the past have revealed serotonin to play a role in regulating the development and maturation of the mammalian brain, largely through the release of the astroglial protein S-100β. S-100β plays a role in neurite extension, microtubule and dendritic stabilization and regulation of the growth associated protein GAP-43, all of which are key elements in the production of synapses. Depletion of serotonin, and thus of S-100β, during synaptogenesis should lead to a loss of synapses and the behaviors dependent on those synapses. The current study was undertaken to test this hypothesis. In order to assess the influence of serotonin we have looked at the synaptic density in the adult after depletion, by using immunodensitometry of synaptic markers (synaptophysin and MAP-2) and by studying behaviors thought to be highly dependent on synaptic plasticity and density. Male Sprague–Dawley rats were depleted of serotonin on postnatal days (PND) 10–20 by treating with the tryptophan hydroxylase inhibitor parachlorophenylalanine (PCPA; 100 mg/kg, s.c.). On PND's 30 and 62, animals were perfused for immunodensitometry. Littermates were used for behavioral testing. At PND 55–62, the animals were tested in an interchangeable maze with olfactory cues and in an eight-arm radial maze. Our results show a loss of both synaptic markers in the hippocampus on PND 30. At PND 62, the only remaining loss was of the dendritic marker MAP-2. The animals had deficits in both behaviors tested, suggestive of spacial learning deficits and of the failure to extinguish learned behaviors or to re-learn in a new set. Our findings show the long-term consequences of interfering with the role of serotonin in brain development on the morphology and function of the adult brain. These findings may have implications for human diseases, including schizophrenia, thought to be related to neurodevelopmental insults such as malnutrition, hypoxia, viruses or in utero drug exposure. Moreover, they provide further insights into the functioning of serotonin and S-100β in development and aging.     

实验性脑出血后脑水肿的动态变化及其与MMP-9的关系

目的探讨脑出血后脑水肿和MMP-9表达的动态变化,并初步探讨其关系。方法健康雄性Wistar大鼠56只,将动物随机分成假手术组和脑出血组,大鼠尾壳核区注入自体非肝素抗凝动脉血建立脑出血模型,采用干湿重法测量脑组织水含量;免疫组织化学方法观察术后不同时间点MMP-9的动态变化。结果血肿形成后脑水肿产生迅速,从脑出血后3h开始增加,48~72h达高峰;脑出血后12h时,血肿周围组织中开始出现大量的深棕黄色阳性染色细胞,术后72h达高峰,以后逐渐下降,至120h时仍维持在较高水平。结论脑出血后脑水肿可能与MMP-9的活化有关。     

Gradients of cellular maturation and synaptogenesis in the superior colliculus of the fetal rhesus monkey

Light (LM) and electron microscopic (EM) qualitative and quantitative analyses were employed to determine the tempo and spatial gradients of synaptogenesis and cellular differentiation in the superficial superior colliculus (SC) of the rhesus monkey between embryonic (E) days E47 and E84. By E47, a majority of the neurons of the prospective superficial gray layer (SGS) have arrived at their final positions and contribute to a uniform band of small, darkly Nissl-stained neurons at the outer surface of the SC. By E54, cells in the middle of the rostral pole of the superficial SC become considerably larger, paler staining, and less densely packed than the more medially or laterally located cells. These regional differences, which extend posteriorly through about the middle of the SC at this age, are evident on both the LM and EM levels and were confirmed by a quantitative EM analysis of the cytodifferentiation and synaptogenesis in the SGS. Several overlapping EM probes made across the medial, middle, and lateral regions of the SGS at each of three coronal levels reveal consistently more developed neuropil and smaller amounts of extracellular space in the middle region than in the medial and lateral portions of the more anterior SC. Further, the densities of synapses, both in terms of synapses/micron2 of total cross-sectional area and synapses/micron2 of neuropil alone, are also higher in the middle than the peripheral regions. Most of the middle-peripheral differences found in the mid-E50s are still evident by the early E60s, but have disappeared by midgestation (E80s). The present results are interpreted to indicate that the middle region of the SGS at a given transverse level begins to mature significantly earlier than the medial or lateral areas. Since our previous 3H-thymidine analysis (Cooper and Rakic, '81a) failed to reveal significant regional variation in the time of neuron origin in the superficial SC, the observed spatiotemporal gradients of neuronal maturation in the primate SGS probably do not arise from underlying gradients of cellular proliferation.     

MMP-2-PEX与MMP-2在侵袭性垂体腺瘤中的表达及意义

目的研究基质金属蛋白酶-2在C端的血红素样结构域(MMP-2-PEX)和基质金属蛋白酶-2(MMP-2)在侵袭性垂体腺瘤中的表达及其意义。方法用逆转录酶-聚合酶链反应(RT-PCR)法检测116例垂体腺瘤标本的MMP-2-PEX及MMP-2的表达,分析其与侵袭性垂体腺瘤的关系及两者之间的相关性。结果侵袭性垂体腺瘤组MMP-2-PEX mRNA表达较非侵袭性垂体腺瘤组显著降低(P<0.01)。侵袭性垂体腺瘤组的MMP-2 mRNA表达明显高于非侵袭性垂体腺瘤组(P<0.01)。侵袭性垂体腺瘤组中MMP-2-PEX mRNA表达与MMP-2 mRNA表达呈负相关(r=-0.66,P<0.05),而非侵袭性腺垂体腺瘤组中无相关性(r=-0.22,P>0.05)。结论 MMP-2-PEX低表达及MMP-2高表达与垂体腺瘤的侵袭性密切相关,MMP-2-PEX及MMP-2可以作为垂体腺瘤侵袭性的重要参考指标。     

凝血酶对大鼠脑内MMP-9、MMP-2表达的影响

目的探讨凝血酶对大鼠脑内MMP-9、MMP-2表达的影响。方法Wistar大鼠随机分为假手术组及实验组。实验组脑内注入凝血酶,在不同时间点采用干湿重法测脑水含量,免疫组化方法检测脑内MMP-9、MMP-2的表达。假手术组注入等量生理盐水。结果脑组织水含量在凝血酶注入后6h开始增加,3d达高峰。MMP-9阳性细胞在注射凝血酶后6h即开始表达增加,与对照组相比差异显著(P<0.01),3d达高峰,随后持续下降。阳性微血管数也有相似的变化趋势。MMP-2阳性细胞在注射凝血酶后1d才开始有少量表达,后持续增多,5d达高峰,随后有所下降,但14d仍有明显表达,与对照组相比差异显著(P<0.01)。阳性微血管数也有相似的变化趋势。结论凝血酶在脑出血后脑水肿及脑组织损伤中起了关键的作用,MMP-9、MMP-2参与了急性期脑水肿、炎症反应等过程,MMP-2在损伤修复中可能有重要作用。     

大鼠实验性脑出血后脑水肿与MMP-9表达的关系及依达拉奉干预效应的研究

目的 探讨脑出血后脑水肿和MMP-9表达的动态变化及依达拉奉的干预效应.方法 采用立体定向技术制作大鼠脑出血模型,干湿重法测量脑组织含水量和免疫组化法测定脑组织MMP-9的表达.结果 与假手术组比较,脑出血12h时脑组织含水量明显增加(P＜0.05), 72h时达到高峰,随后逐渐下降, 7d时仍高于假手术组(P＜0.05).出血组大鼠脑含水量与血肿周围MMP-9阳性细胞数呈正相关(r=0.846, P=0.034),且差异有统计学意义.(3)治疗组脑含水量和MMP-9阳性细胞数与假手术组比较差异有统计学意义,与出血组比较差异亦有统计学意义(P＜0.05).结论 MMP-9参与了脑出血后脑水肿的形成,依达拉奉对脑水肿有抑制作用.     

Exposure to interferon-gamma during synaptogenesis increases inhibitory activity after a latent period in cultured rat hippocampal neurons

Certain disorders of the nervous system may have their origin in disturbances in the development of synaptic connections and network structure that may not become overt until later in life. As inflammatory cytokines can influence synaptic activity in neuronal cultures, we analysed whether cytokine exposure during synaptogenesis can lead to imbalances in a neuronal network. Short-term application of interferon-gamma (IFN-gamma), but not tumour necrosis factor-alpha, during peak synaptogenesis (but not before or after) in Sprague-Dawley rat hippocampal cultures, caused both a decrease in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) and an increase in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs). These effects were only detected in recordings made weeks later. This was not due to a depression of glutamatergic synapses or to a change in the relative number of neurons containing glutamic acid decarboxylase (GAD). There was an increase in the average amplitude of miniature IPSCs, and in GAD-expressing neurons the amplitude of miniature EPSCs were larger as well as the responses to glutamate. This indicates that IFN-gamma-treatment induced increased inhibition via postsynaptic changes. These effects of IFN-gamma treatment were not observed when neuronal nitric oxide synthase was inhibited. Our study therefore shows that exposure to IFN-gamma during a restricted period of development, which coincides with the peak of excitatory synaptogenesis, can cause progressive changes in synaptic activity in the network. Thus, cytokine exposure at a critical period of development may constitute a 'hit-and-run' mechanism for certain nervous system disorders that become manifest after a latency period.     

c-Jun在颅内动脉瘤中的表达及对MMP-9表达调控作用的研究

目的检测c-Jun在颅内动脉瘤中的表达及探讨其对基质金属蛋白酶-9（MMP-91表达调控的意义。方法对15例颅内动脉瘤标本和6例非脑血管病患者的正常脑血管应用免疫组化SP法和实时荧光定量RT-PCR法分别检测脑血管壁组织内c-Jun免疫活性和MMP-9mRNA的表达水平。结果c-Jun免疫活性在颅内动脉瘤壁组织内为1．92±0．51，正常脑血管壁内为0．17±0．41，二者有显著性差异（P〈0．01）。动脉瘤壁组织中MMP-9mRNA的表达是正常血管的10．06倍（P〈0．01）。颅内动脉瘤壁组织内c-Jun的免疫活性和MMP-9mRNA的表达呈正相关（r=．818，P〈0．001）。结论活化后的c-Jun可能通过其结构域内MMP-9结合位点启动MMP-9大量转录而参与颅内动脉瘤的发病机制。