大鼠脑内基质金属蛋白酶-9表达及其在海马依赖的学习记忆中的作用
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摘要
目的:探讨Y迷宫训练后大鼠脑内MMP-9表达及其在海马依赖的学习记忆中的作用。方法:3月龄雄性SD大鼠,随机分成对照组(CON,n=12)和Y迷宫训练组(T,n=60),后者又根据训练天数和处死时间分成5组。计算大鼠在Y迷宫训练中的连续正确反应次数,观察其学习能力;用Western blot检测各组动物不同脑区MMP-9前体(proMMP-9)和活性形式(actMMP-9)的蛋白表达,用免疫组化学和RT-PCR分别检测海马区MMP-9蛋白和mRNA的表达。探讨MMP-9表达与其学习能力的相关性。结果:1)Y迷宫训练早期,大鼠海马区出现actMMP-9蛋白水平一过性增加,同时其MMP-9mRNA表达也相应升高;而额叶区未出现类似变化。2)Y迷宫第一天训练后4h大鼠海马区actMMP-9表达水平与其第一天训练成绩(平均连续正确反应次数)呈正相关(p＜0.05)。结论:actMMP-9可能参与了大鼠Y迷宫的学习过程。
Objective: To study matrix metalloproteinase -9 (MMP-9)expression in the rat brain after Y maze training and its role in the hippocampal-dependent learning and memory. Methods: Male Sprague-Dawley rats(3 months old) were assigned randomly to control group (CON, n=12) and training group (T, n=60). The training group was also divided into five groups. Rats were evaluated for their learning ability in Y maze by measuring the number of continuous correct responses in finding the safe place with repeated trials. Then two forms of MMP-9(proMMP-9 and actMMP-9) protein were detected and quantitated from different rat lobs and in different time by Western blot. The expression of MMP-9 and MMP-9mRNA were detected by immumohistochemistry and RT-PCR, respectively. Furthermore, the correlation between the learning ability of rats in Y maze training and the levels of MMP-9 in hippocampus was evaluated. Results: 1) It was observed that hippocampal actMMP-9 increased transiently in the early time during Y maze training as assessed by Western blotting and mRNA analysis. But the same appearances were not found in prefrontal cortex of all the groups. 2) Four hours after the first day training, levels of actMMP-9 in the hippocampus of rats were significantly correlated with their numbers of the continuous correct responses. Conclusion: ActMMP-9 may involved in the hippocampal-dependent learning during Y maze training.
Objective: To study matrix metalloproteinase -9 (MMP-9)expression in the rat brain after Y maze training and its role in the hippocampal-dependent learning and memory. Methods: Male Sprague-Dawley rats(3 months old) were assigned randomly to control group (CON, n=12) and training group (T, n=60). The training group was also divided into five groups. Rats were evaluated for their learning ability in Y maze by measuring the number of continuous correct responses in finding the safe place with repeated trials. Then two forms of MMP-9(proMMP-9 and actMMP-9) protein were detected and quantitated from different rat lobs and in different time by Western blot. The expression of MMP-9 and MMP-9mRNA were detected by immumohistochemistry and RT-PCR, respectively. Furthermore, the correlation between the learning ability of rats in Y maze training and the levels of MMP-9 in hippocampus was evaluated. Results: 1) It was observed that hippocampal actMMP-9 increased transiently in the early time during Y maze training as assessed by Western blotting and mRNA analysis. But the same appearances were not found in prefrontal cortex of all the groups. 2) Four hours after the first day training, levels of actMMP-9 in the hippocampus of rats were significantly correlated with their numbers of the continuous correct responses. Conclusion: ActMMP-9 may involved in the hippocampal-dependent learning during Y maze training.
引文
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[23]Dityatev A, Schachner M. Extracellular matrix molecules and synaptic plasticity [J]. Nat Rev Neurosci, 2003,4( ):456-468.
[24]Shiosaka S. Serine proteases regulating synaptic plasticity [J]. Anat Ser Int Inst, 2004,79( ):137-144.
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[2]Zhao BQ, Wang S, Kim HY, et al. Role of matrix metalloproteinases in delayed cortical responses after stroke[J]. Nat Med, 2006,120:441-445.
[3]Hsu JY, Mckeon R, Goussev S, et al. Matrix metalloproteinase 2 facilitates wound healing events that promote functional recovery after spinal cord injury[J]. Neurosci, 2006,26():9841-9850.
[4]Cuzner ML, Gveric D, Strand C, et al. The expression of tissue-type plasminogen activator, matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution[J]. Neutropathol Exp Neurol, 1996,55():1194-1204.
[5]Lorenzl S, Albers DS, Chirichigno JW, et al. Elevated levels of matrix metalloproteinases-9 and -1 of tissue inhibitors of MMPs, TIMP-1 and TIMP-2 in postmortem brain tissue of progressive supranuclear palsy[J]. Neurlo Sci, 2004,218():39-45.
[6]Pagenstecher A, Stalder AK, Kincaid CL, et al. Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflannatory states[J[. Am J Pathol, 1998,152():729-741.
[7]Leszek K, Joanna LD, Sylwia S. Matrix metalloproteinases in the adult brain physiology: a link between c-Fos, AP-1 and remodeling of neuronal connections? [J] ENBO J, 2002,210:6643-6648.
[8]Flannery C.R., MMPs and ADANTSs: functional studies. Front. Biosci.2006; 11:544-569
[9]Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases [J]. Pathol, 2003,200(), 448-464.
[10]Bosman FT, Stamenkovic I. Functional structure and composition of the extracellular matrix[J]. The Journal of Pathology, 2003,200(4):423-428.
[11]Wright JW, Harding JW. The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory[J]. Progress in Neurobiology, 2004,72(4):263-293.
[12]Dityatev A, Schachner M. Extracellular matrix molecules and synaptic plasticity. Nature Reviews Neuroscience, 2003,4(6):456-468.
[13]Frankland PW, Bontempi B. The organization of recent and remote memories. Nature Reviews Neuroscience, 2005,6(2):119-130.
[14]Oh LY, Larsen PH, Krekoski CA, et al. Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes[J]. Neurosci, 1999,19( ):8464-8475.
[15]Vaillant C, Meissirel C, Mutin M, et al. MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum[J]. Mol Cell Neurosci, 2003,24():395-408.
[16]Ogier C, Bernard A, Chollet AM, et al. Matrix metalloproteinase-2(MMP-2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins[J]. Glia, 2006,54( ):272-284.
[17]Orve J, Montero I, Rodriguez JA, et al.Independent association of matrix metalloproteinase-10, cardiovascular risk factors and subclinical atherosclerosis[J]. Thromb Haemost,2007,5():91-97.
[18]Falo MC, Fillmore HL, Reeves TM, et al. Marrix metalloproteinase-3 expression profile differdnriates adaptive and maladaptive synaptic plasticity induced by traumatic brain injury[J]. Neurosci Res, 2008,84( ):761-781.
[19]Lucivem V, Prontera M, Mezzapesa DM, et al. Different roles of matrix metalloproteinases-2 and-9 after human ischaemic stroke[J]. Neurol Sci, 2007, 28( ): 165-170.
[20] Rosen A, Onega AA, Alvarez SJ, et al. Increased brain expression of matrix metallopmteinase-9 after ischemic and hemorrhagic human stroke[J]. Stroke, 2006, 37(): 1399-1406.
[21] Magnoni S, Baker A, George SJ, et al. Differential alterations in the expression and activity of matrix metalloproteinases-2 and-9 after transient cerebral ischemia in mice [J].Neurobiology of Disease,2004,17():188-197.
[22]Nordqvist AS,Smurawa H,Mathiesen T.Expression of matrix metallopmtcinases2 and 9 in meningiomas associated with different degrees of brain invasiveness and edema[J].J Neurosurg,2001,95(5):839-844.
[23]Wright JW,Brown TE,Harding JW.Inhibition of hippocampal matrix metalloproteinase-3 and -9 disrupts spatial memory.Neural Plasticity,2007,2007:73813-73821
[24]Starla E,Meighan PC,Meighan PC,et al.Effects of extracellular matrix-degrading proteases matrix metalloproteinases-3 and -9 on spatial learning and synaptic plasticity[J].Neurochem,2006,96():1227-1241.
[25]Taishi P,Sanchez C,Wang Y,et al.Conditions that affect sleep alter the expression of molecules associated with synaptic plasticity[J].Am J Physiol Regul Integr Comp Physiol,2001,281():R839-845.
[26]孟海云,李福琴,赵琳琳等。MMP-9、存活素在妊娠滋养细胞疾病中的表达及其临床意义。哈尔滨医科大学学报,2008,42(3):293-295。
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