先天性巨细胞病毒神经系统感染对小鼠海马区突触素、神经颗粒素表达及学习记忆的影响
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摘要
目的观察先天性巨细胞病毒(CMV)神经系统感染后海马区突触素、神经颗粒素表达的改变及对学习记忆能力的影响。方法 56只新生BALB/C小鼠(1日龄)随机数余数分组法随机分为感染组和对照组,每组28只,感染组于0日龄颅内注射小鼠巨细胞病毒,建立先天性巨细胞病毒神经系统感染模型,对照组颅内接种等量的病毒溶媒。分别于3日、15日、30日龄(每组7只)采用免疫组化技术半定量检测两组小鼠海马区突触素和神经颗粒素表达水平,于30日龄行物体识别实验检测剩余小鼠(每组7只)学习记忆能力。结果感染组小鼠海马区3日龄、15日龄、30日龄的突触素表达光密度值分别为(74.71±5.96)、(97.71±8.64)、(116.70±12.98),明显低于同期对照组的(87.86±4.53)、(127.90±5.27)、(158.00±10.07),差异均具有统计学意义(P<0.05);感染组小鼠海马区3日龄、15日龄、30日龄的神经颗粒素表达光密度值分别为(47.14±3.44)、(60.86±7.71)、(69.86±6.09),明显低于同期对照组的(54.29±5.06)、(80.86±7.01)、(97.57±6.95),差异均具有统计学意义(P<0.05);感染组小鼠30日龄的分辨指数为(0.384 3±0.097 3),明显低于同期对照组的(0.552 9±0.081 6),差异具有统计学意义(P<0.05)。结论先天性巨细胞病毒感染可导致发育过程中的小鼠海马突触素和神经颗粒素表达水平降低,学习记忆能力下降。
Objective To study the effect of congenital cytomegalovirus(CMV) infection on synaptophysin and neurogranin of hippocampus and cognition in mice. Methods The models of congenital CMV infection on neonate mice were built, and the fetal BALB/C mice were randomly divided into the infectious group(n=28) and the control group(n=28) on the day of delivery. The fetal mice in infectious group were intracranial inoculated with CMV suspension, and the fetal mice in control group were inoculated with equivalent volume of virus solvent. The expression of the synaptophysin and neurogranin were observed on the 3rd, 15 th, 30 thdays post-inoculation by immunohistochemical SP method. On the 30 thday post-inoculation, the learning and memory ability was detected by Object Recognition Test. Results The optical density value of synaptophysin expression in the hippocampal area of the infectious group on the 3rd,15 th, 30 thdays post-inoculation were(74.71±5.96),(97.71±8.64),(116.70±12.98), significantly lower than(87.86±4.53),(127.90±5.27),(158.00±10.07) in the control group(P<0.05). The optical density value of neurogranin expression in the hippocampal area of the infectious group on the 3rd, 15 th, 30 thdays post-inoculation were(47.14 ± 3.44),(60.86 ± 7.71),(69.86±6.09), significantly lower than(54.29±5.06),(80.86±7.01),(97.57±6.95) in the control group(P<0.05). The resolution index of 30-day old mice in the infectious group was(0.384 3±0.097 3), significantly lower than(0.552 9±0.0816) in the control group(P<0.05). Conclusion Congenital CMV infection could induce the decrease of the expression of synaptophysin and neurogranin of hippocampus in developing fetal mice, and results in declined learning and memory ability.
Objective To study the effect of congenital cytomegalovirus(CMV) infection on synaptophysin and neurogranin of hippocampus and cognition in mice. Methods The models of congenital CMV infection on neonate mice were built, and the fetal BALB/C mice were randomly divided into the infectious group(n=28) and the control group(n=28) on the day of delivery. The fetal mice in infectious group were intracranial inoculated with CMV suspension, and the fetal mice in control group were inoculated with equivalent volume of virus solvent. The expression of the synaptophysin and neurogranin were observed on the 3rd, 15 th, 30 thdays post-inoculation by immunohistochemical SP method. On the 30 thday post-inoculation, the learning and memory ability was detected by Object Recognition Test. Results The optical density value of synaptophysin expression in the hippocampal area of the infectious group on the 3rd,15 th, 30 thdays post-inoculation were(74.71±5.96),(97.71±8.64),(116.70±12.98), significantly lower than(87.86±4.53),(127.90±5.27),(158.00±10.07) in the control group(P<0.05). The optical density value of neurogranin expression in the hippocampal area of the infectious group on the 3rd, 15 th, 30 thdays post-inoculation were(47.14 ± 3.44),(60.86 ± 7.71),(69.86±6.09), significantly lower than(54.29±5.06),(80.86±7.01),(97.57±6.95) in the control group(P<0.05). The resolution index of 30-day old mice in the infectious group was(0.384 3±0.097 3), significantly lower than(0.552 9±0.0816) in the control group(P<0.05). Conclusion Congenital CMV infection could induce the decrease of the expression of synaptophysin and neurogranin of hippocampus in developing fetal mice, and results in declined learning and memory ability.
引文
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[7]陈娟娟,陈素华,冯燕,等.胎盘接种小鼠巨细胞病毒对仔鼠物体识别能力的影响[J].中国优生与遗传杂志, 2007, 15(2):30-31.
[8] RESSLER KJ, PASCHALL G, ZHOU XL, et al. Regulation of synaptic plasticity genes during consolidation of fear conditioning[J]. J Neurosci, 2002, 22(18):7892-7902.
[9] dE KLOET ER, MEIJER OC, dE NICOLA AF, et al. Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation[J]. Front Neuroendocrinol,2018, 4(49):124-145.
[10] DECKWERTH TL, ELLIOTT JL, KNUDSON CM, et al. BAX is required for neuronal death after trophic factor deprivation and during development[J]. Neuron, 1996, 17(3):401-411.
[11] MERIGHI A. Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain[J]. Expert Opin Ther Targets, 2016, 20(2):193-208.
[12] MAGALH?ES RC, PIMENTA LP, BARBOSA IG, et al. Inflammator molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates:a systematic review[J].Int J Dev Neurosci, 2018, 4(65):29-37.
[13] KWAK M, YUM MS, YEH HR, et a1. Brain magnetic resonance imaging findings of congenital cytomegalovirus infection as a prognostic factor for neurological outcome[J]. Pediatr Neurol, 2018, 1(83):14-18.
[14] CASALETTO KB, ELAHI FM, BETTCHER BM, et al. Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers[J]. Neurology, 2017, 89(17):1782-1788.
[15]李雨峰,吴莹,程明,等.康复训练对脑梗死大鼠认知功能、海马内突触素和神经颗粒素表达的影响[J].中国康复理论与实践, 2012,18(1):15-18.
[16] JONES KJ, TEMPLET S, ZEMOURA K, et al. Rapid, experience-dependent translation of neurogranin enables memory encoding[J].Proc Natl Acad Sci USA, 2018, 115(25):E5805-E5814.
[17] FOWLER KB, BOPPANA SB. Congenital cytomegalovirus infection[J]. Semin Perinatol, 2018, 42(3):149-154.
[18] ZOU F, LU ZT, WANG S, WU S, et al. Human cytomegalovirus UL141 protein interacts with CELF5 and affects viral DNA replication[J]. Mol Med Rep, 2018, 17(3):4657-4664.
[19]王晗,李廷栋,郭小怡,等.巨细胞病毒实验室检测方法研究进展及其用于新生儿筛查的可行性[J].临床儿科杂志, 2018, 36(3):221-226.
[2]喻欢,黄悦,卫飞雪,等.新生儿先天性巨细胞病毒感染的研究进展[J].中国妇幼保健, 2018, 33(14):3345-3349.
[3] GANTT S, MARCHANT A, BOPPANA SB. Higher expectations for a vaccine to prevent congenital cytomegalovirus infection[J]. J Virol, 2018, 92(15):pii:e00764-18.
[4] LERUEZ-VILLE M, VILLE Y. Fetal cytomegalovirus infection[J].Best Pract Res Clin Obstet Gynaecol, 2017, 38:97-107.
[5] MCVOY MA, LEE R, SACCOCCIO FM, et al. A cytomegalovirus DNA vaccine induces antibodies that block viral entry into fibroblasts and epithelial cells[J]. Vaccine, 2015, 33(51):7328-7336.
[6] GORDON SL, HARPER CB, SMILLIE KJ, et al. A fine balance of synaptophysin levels underlies efficient retrieval of synaptobrevin II to synaptic vesicles[J]. PLoS One, 2016, 11(2):e0149457.
[7]陈娟娟,陈素华,冯燕,等.胎盘接种小鼠巨细胞病毒对仔鼠物体识别能力的影响[J].中国优生与遗传杂志, 2007, 15(2):30-31.
[8] RESSLER KJ, PASCHALL G, ZHOU XL, et al. Regulation of synaptic plasticity genes during consolidation of fear conditioning[J]. J Neurosci, 2002, 22(18):7892-7902.
[9] dE KLOET ER, MEIJER OC, dE NICOLA AF, et al. Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation[J]. Front Neuroendocrinol,2018, 4(49):124-145.
[10] DECKWERTH TL, ELLIOTT JL, KNUDSON CM, et al. BAX is required for neuronal death after trophic factor deprivation and during development[J]. Neuron, 1996, 17(3):401-411.
[11] MERIGHI A. Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain[J]. Expert Opin Ther Targets, 2016, 20(2):193-208.
[12] MAGALH?ES RC, PIMENTA LP, BARBOSA IG, et al. Inflammator molecules and neurotrophic factors as biomarkers of neuropsychomotor development in preterm neonates:a systematic review[J].Int J Dev Neurosci, 2018, 4(65):29-37.
[13] KWAK M, YUM MS, YEH HR, et a1. Brain magnetic resonance imaging findings of congenital cytomegalovirus infection as a prognostic factor for neurological outcome[J]. Pediatr Neurol, 2018, 1(83):14-18.
[14] CASALETTO KB, ELAHI FM, BETTCHER BM, et al. Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers[J]. Neurology, 2017, 89(17):1782-1788.
[15]李雨峰,吴莹,程明,等.康复训练对脑梗死大鼠认知功能、海马内突触素和神经颗粒素表达的影响[J].中国康复理论与实践, 2012,18(1):15-18.
[16] JONES KJ, TEMPLET S, ZEMOURA K, et al. Rapid, experience-dependent translation of neurogranin enables memory encoding[J].Proc Natl Acad Sci USA, 2018, 115(25):E5805-E5814.
[17] FOWLER KB, BOPPANA SB. Congenital cytomegalovirus infection[J]. Semin Perinatol, 2018, 42(3):149-154.
[18] ZOU F, LU ZT, WANG S, WU S, et al. Human cytomegalovirus UL141 protein interacts with CELF5 and affects viral DNA replication[J]. Mol Med Rep, 2018, 17(3):4657-4664.
[19]王晗,李廷栋,郭小怡,等.巨细胞病毒实验室检测方法研究进展及其用于新生儿筛查的可行性[J].临床儿科杂志, 2018, 36(3):221-226.