转铁蛋白受体1敲除导致海马神经元突触传递和可塑性的缺陷
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摘要
转铁蛋白受体(transferrin receptor, TfR)存在于许多细胞的表面,现已发现两种转铁蛋白受体,分别是转铁蛋白受体1(TfR1)和转铁蛋白受体2(TfR2)。 TfR1在中枢神经系统(central neuron system, CNS)中广泛存在,但TfR2几乎没有,因此我们研究的对象是CNS中的TfR1。 TfR1在生物体中的主要功能是介导含铁的铁蛋白从细胞外进入细胞内。比如TfR1在CNS通过转铁蛋白(transferrin, Tf)—fRl复合物负责铁的运输。目前TfR1在神经元突触传递和可塑性中的作用尚不清楚。突触是神经元之间的接触点和信息交流场所,其传递效能存在可调节性,被称为突触可塑性。大脑海马CA1区至CA3区的信号传导环路是大脑海马区突触可塑性的主要产生位点,并且已经证明参与了许多生理过程。本论文以大脑海马CA3区锥体细胞的Schaffer侧支接受CA1区锥体细胞的信号输入这一环路作为研究模型,采用场兴奋性突触后电位技术和全细胞膜片钳技术,探索大脑海马区在TfRl敲除后对突触传递效能和突触可塑性的影响。
实验中,我们利用条件敲除的Nestin Cre-TfR1小鼠,检测海马CA1区锥体神经元的突触传递,受体表达以及长时程突触可塑性。我们的结果显示,TfR1敲除后谷氨酸能突触前释放率下降,突触后电流下降,但突触后NMDA受体和AMPA受体的比值没有改变。我们进一步利用场电位记录了在CA1区通过100Hz和TBS刺激诱导的LTP,发现两者在TfRl敲除动物中均下调。这些结果中提示TfR1对于海马CA1神经元突触传递和可塑性具有重要作用。
Transferrin receptors exist in many cells' surface. Two types of transferrin receptors have been found in organisms, one is transferrin receptor1(TfR1) and the other one is transferrin receptor2(TfR2). The former widely distributes in the brain while the latter is rare, so we focus to the research of TfR1. The main function of TfR1in organism is that it can deliver ferroprotein into cells from outside of the cells. For example, in central nervous system (CNS), TfR1-mediated endocytosis transfers transferring (Tf)-iron complex to intracellular. Thus it can regulate the growth of cell. But its effect on neurons synaptic transmission and synaptic plasticity is not clear at present. As the major contact point and communication place between neurons, the synapse is regarded as the major location where learning and memory happen. The efficiency of synaptic transmission can be modified, so we called it as synaptic plasticity, which could persist from several hours to several days. Schaffer collateral of CA3pyramidal cells (CA3) receives inputs from CA1pyramidal cells (CA1). This circuit involves into many physiologic processes and is regarded as the major location where synaptic plasticities in hippocampal of cerebral happen. In this dissertation, in order to obtain a breakthrough on the function of TfRl in CNS, we investigated whether TfR1could affect synaptic transmission and plasticities by fEPSP and whole cell patch clamp techniques using the CA1-CA3circuit of hippocampal model.
In our experiment, we detected the synaptic transmission, receptor expression and long term synaptic plasticity of CA1vertebral neurons in hippocampal area of conditional knock-out Nestin Cre-TfR1mouse. The results showed that glutamatergic presynaptic release rate decreased after TfR1knocking out. Although postsynaptic current declined, the ratio between postsynaptic NMDA receptor and AMPA receptor did not change. Furthermore, we recorded the long term potentiation (LTP) induced by100Hz (HFS) and TBS stimulation in CA1, and found that both LTP in TfR1knockout animals were down. So we concluded that TfRl played an important role in the growth of hippocampal CA1neurons.
实验中,我们利用条件敲除的Nestin Cre-TfR1小鼠,检测海马CA1区锥体神经元的突触传递,受体表达以及长时程突触可塑性。我们的结果显示,TfR1敲除后谷氨酸能突触前释放率下降,突触后电流下降,但突触后NMDA受体和AMPA受体的比值没有改变。我们进一步利用场电位记录了在CA1区通过100Hz和TBS刺激诱导的LTP,发现两者在TfRl敲除动物中均下调。这些结果中提示TfR1对于海马CA1神经元突触传递和可塑性具有重要作用。
Transferrin receptors exist in many cells' surface. Two types of transferrin receptors have been found in organisms, one is transferrin receptor1(TfR1) and the other one is transferrin receptor2(TfR2). The former widely distributes in the brain while the latter is rare, so we focus to the research of TfR1. The main function of TfR1in organism is that it can deliver ferroprotein into cells from outside of the cells. For example, in central nervous system (CNS), TfR1-mediated endocytosis transfers transferring (Tf)-iron complex to intracellular. Thus it can regulate the growth of cell. But its effect on neurons synaptic transmission and synaptic plasticity is not clear at present. As the major contact point and communication place between neurons, the synapse is regarded as the major location where learning and memory happen. The efficiency of synaptic transmission can be modified, so we called it as synaptic plasticity, which could persist from several hours to several days. Schaffer collateral of CA3pyramidal cells (CA3) receives inputs from CA1pyramidal cells (CA1). This circuit involves into many physiologic processes and is regarded as the major location where synaptic plasticities in hippocampal of cerebral happen. In this dissertation, in order to obtain a breakthrough on the function of TfRl in CNS, we investigated whether TfR1could affect synaptic transmission and plasticities by fEPSP and whole cell patch clamp techniques using the CA1-CA3circuit of hippocampal model.
In our experiment, we detected the synaptic transmission, receptor expression and long term synaptic plasticity of CA1vertebral neurons in hippocampal area of conditional knock-out Nestin Cre-TfR1mouse. The results showed that glutamatergic presynaptic release rate decreased after TfR1knocking out. Although postsynaptic current declined, the ratio between postsynaptic NMDA receptor and AMPA receptor did not change. Furthermore, we recorded the long term potentiation (LTP) induced by100Hz (HFS) and TBS stimulation in CA1, and found that both LTP in TfR1knockout animals were down. So we concluded that TfRl played an important role in the growth of hippocampal CA1neurons.
引文
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[2]Alger, B.E., and Teyler, T.J. Long-term and short-term plasticity in the CA1, CA3, and dentate regions of the rat hippocampal slice. Brain Res,1976,110,463-480.
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[7]Blanpied TA, Scott DB, and Ehlers MD. Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron,2002, 24;36(3):435-49
[8]Morgan, E. H.. Transferrin, biochemistry, physiology and clinical significance. Mol. Aspects Med,1981,4:1-123.
[9]Moos T, Morgan EH. Kinetics and distribution of [59Fe-125I] transferrin injected into the ventricular system of the rat. Brain Res,1998,790(1-2):115-28
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[11]Qian ZM, Pu YM, Tang PL, et al. Transferrin-bound iron uptake by the cultured cerebellar granule cells. Neurosci Letters,1998,251(1):9-12
[12]Byrne SL, Chasteen ND, Steere AN, et al. The unique kinetics of iron release from transferrin: the role of receptor, lobe-lobe interactions, and salt at endosomal pH. J Mol Biol,2010,396(1):130-40
[13]Macedo MF, de Sousa M. Transferrin and the transferring receptor:of magic bullets and other concerns. Inflamm Allergy Drug Targets,2008,7(1):41-52
[14]Amaral DG and Witter MP. The three-dimensional organization of the hippocam-pal formation:a review of anatomical data. Neuroscience,1989; 31:571-591
[15]Anderson P, Bliss VP, Skrede KK. Lamellar organization of hippocampal excitatory pathways. Expl Brain Res,1971;13:222-238
[16]Amaral DG. Emerging principles of intrinsic hippocampal organization. Curr Opin Neurobiol,1993; 3:225-229
[17]Gloveli T, Dugladze T, Saha S, et al. Differential involvement of oriens /pyrami-dale interneurons in hippocampal network oscillations in vitro. J physiol,2005; 562:131-147
[18]Bliss T V P, Gradner-Medwin A R. Long-lasting potentiation of synaptic transmission in the dentate area of the unanesthetized rabbit following stimulation of the perforant path. J Physiol,1973,232(2):357.
[19]Scharfman H E. Postsynaptic firing during reptitive stimulation is required for long-term potentiation in hippocampus. Brain Res,1985,331(1):267.
[20]Malinow, R., Mainen, Z. F. & Hayashi, Y. LTP mechanisms:from silence to four-lane traffic. Curr. Opin. Neurobiol,2000,10,352-357.
[21]Soderling TR, Derkach VA. Postynaptic protein phosphorylation and LTP. Trends in Neuroscience,2000,23:75-78.
[22]Zakharenko, S. S., Zablow, L. & Siegelbaum, S. A. Visualization of changes in presynaptic function during long-term synaptic plasticity. Nature Neurosci,2001,4, 711-717.
[23]Per A., Richard M., David A., et al. The hippocampus book, [M]; Oxford:Oxford University Press,2007:305-314.
[24]Andersen P, Andersson SA, and Lomo T. Patterns of spontaneous rhythmic activity within various thalamic nuclei. Nature,1966,20; 211(5051):888-9.
[25]Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol,2000,20(1):77-95.
[26]Byrne SL, Chasteen ND, Steere AN, et al. The unique kinetics of iron release from transferrin:the role of receptor, lobe-lobe interactions, and salt at endosomal pH. J Mol Biol,2010,396(1):130-140.
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[1]Moos T, Morgan EH. The critical component to establish in vitro BBB model: Pericyte. Brain Res Brain Res Rev,2005,50(2):258-265
[6]Tampanaru-Sarmesiu A, Stefaneanu L, Thapar K, et al. Transferrin and transferrin receptor in human hypophysis and pituitary adenomas. Am J Pathol,1998 152(2):413-422
[7]Kovala AT, Harvey KA, McGlynn P, et al. High-efficiency transient transfection of endothelial cells for functional analysis. FASEB J,2000,14(15):2486-2494
[8]Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol,2000,20(1):77-95
[9]Byrne SL, Chasteen ND, Steere AN, et al. The unique kinetics of iron release from transferrin:the role of receptor, lobe-lobe interactions, and salt at endosomal pH. J Mol Biol,2010,396(1):130-140
[10]Yang WM,Jung KJ,Lee MO, et al. Transient expression of iron transport proteins in the capillary of the developing rat brain. Cell Mol Neurobiol,2011,31(l):93-99
[11]Moos T, Rosengren Nielsen T, Skjorringe T, et al. Iron trafficking inside the brain J Neurochem,2007,103(5):1730-1740
[12]Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol,2006,2(8):406-414
[13]Qian ZM, Liao QK, To Y, et al. Transferrin-bound and transferrin free iron uptake by cultured rat astrocytes. Cell Mol Biol,2000,46(3):541-548
[14]Dornelles AS, Garcia VA, de Lima MN, et al. mRNA expression of proteins involved in iron homeostasis in brain regions is altered by age and by iron overloading in the neonatal period. Neurochem Res,2010,35(4):564-571
[15]Han J,Day JR, Connor JR, et al. Gene Expression of transferrin and transferrin receptor in brains of control vs. iron-deficient rats. Nutritional Neurosci,2003,6 (1):1-10
[16]Visser CC, Voorwinden LH, Crommelin DJ, et al. Characterization and modulation of the transferring receptor on brain capillary endothelial cells. Pharm Res,2004, 21(5):761-769
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