先天性静止性夜盲大鼠视杆双极细胞L-钙通道电生理特征
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摘要
先天性静止性夜盲(congenital stationary night blindness,CSNB)是一类先天性、非进展性、以视网膜视杆信号系统功能障碍为主的眼科疾病,其发病机制尚不完全明确,且缺乏有效治疗手段。我们实验室发现的一种CSNB模式大鼠为编码L-钙通道的Cacna1f基因自然突变所致,主要影响视网膜视杆信号系统,电生理及行为学证明其克服了基因工程诱导模式动物与临床实际差异较大的缺陷,因此可以作为研究CSNB发病机制及视网膜信号回路之间关系的一种新模型。以往研究工作主要集中在视网膜第一级神经元水平(视杆细胞),推测其发病机制为视杆细胞突触末端膜钙通道功能障碍,后者对含递质囊泡释放产生影响,导致视觉信号传导受限而发病。该通道在视杆双极细胞(rod bipolar cells, RBCs)中也有表达,其在CSNB发病中的作用尚未见文献报道。
鉴于双极细胞在视觉信号转导,以及视杆与视锥回路间相互作用中起着非常重要的作用,本实验采用利用全细胞膜片钳技术对本实验室培育的CSNB大鼠RBCsL-钙通道电生理学和通道药理学特征进行观察,并探讨其与视网膜视觉信号传递障碍之间的联系。脊椎动物视网膜有非常相似的解剖结构和生理机能,不同动物的实验结果种群变异性很小,因此研究CSNB钙通道电流特征可为进一步明确这种疾病的发病机制及采取针对性的视觉干预保护措施提供依据。
材料与方法
实验采用本实验室鉴定发现,并建立近交系的CSNB大鼠(F20/F21,4～8周龄)及正常同龄对照SD大鼠,深度麻醉后处死大鼠摘取眼球,利用手动切片机制作视网膜切片,在红外干涉显微成像系统中寻找RBCs胞体,运用全细胞膜片钳模式记录L-钙通道电流;给细胞施加阶跃刺激(从-60 mV除极至0mV,时程200ms),记录程序刺激后细胞静息膜电容(restCm)的变化值(△Cm),并据此计算胞吐系数EI( Exocytotic index);分别施加L-钙通道阻断剂nifedipine和GABA受体阻断剂PTX来观察通道的药理学特征;用应用Axon公司的pClamp8.1软件进行数据测量分析,获取RBCsL-钙通道电生理学指标。在Clampfit上选取有代表性的实验记录,导入到Origin软件进行分析和作图。
结果
1. RBCsL-钙通道电流特征
给细胞施加阶跃刺激和斜坡刺激后,在SD组和CSNB组大鼠的RBCs中均可记录出内向电流,其电生理学特征符合L-钙通道电流特点:在较高除极电位激活;失活缓慢;载流离子为Ca2+:用同等浓度Mg2+代替灌流液中的Ca2+,未能记录到类似电流。
2. L-钙通道药理学特性
特异性L-钙通道阻断剂nifedipine(10μm)可以完全阻断SD组和CSNB组所记录的内向电流。结合其电生理学特征我们可以判定本实验在RBCs所记录到的内向电流为L型钙通道电流。
3. SD大鼠与CSNB大鼠RBCs L-钙通道电流比较SD组大鼠RBCs L-钙通道于-40mV左右开放,通道电流于-20和-30mV之间达到峰值:-33.2±2.5pA(n=20)。CSNB组大鼠RBCs L-钙通道于-20mV和-30mV之间开始激活,通道电流于-15mV左右达峰,峰值为12.2±2.3pA(n=23)。
4. SD大鼠视网膜RBCs的负反馈电流
SD组较强程度除极(-20m和-30mv)时可在Ca2+电流上发现较小的外向的电流(n=11),电流大小与细胞在切片中的位置有关,位置越深外向电流越大。应用GABAA和GABAC受体阻断剂PTX(100μm)能够明显阻断这种外向电流,提示其为为RBCs的突触前GABAA和GABAC受体介导的抑制性突触后电流(inhibitory postsynaptic current ,IPSCS)。而在CSNB组所有记录细胞中均未发现此种外向电流。
5.SD大鼠与CSNB大鼠RBCs胞吐指数差异
给细胞施加阶跃刺激(从-60 mV除极至0mV,时程200ms),记录程序刺激后restCm的变化值(△Cm),并据此计算胞吐系数EI:SD组大鼠restCm为:4146.600±544.202 fF,△Cm为29.600±7.472 fF,EI:0.723±0.199;CSNB组大鼠restCm为:4356.957±549.493 ,△Cm为12.348±6.919 , EI为0.291±0.173。SD组大鼠△Cm较CSNB组大鼠高,EI较CSNB组大鼠大,有明显差异(p<0.01)与对照组比较,CSNB大鼠的△Cm和EI明显降低(p<0.01)。
结论
1.实验在CSNB组和SD组大鼠RBCs中所记录的电流为L-钙通电流;CSNB组大鼠RBCs L-钙通电流峰值明显小于SD组大鼠,推测CSNB大鼠电流强度降低导致胞内,尤其是突触终末的Ca2+浓度降低,难以达到触发正常速率神经递质释放所需要的浓度,因此可能会使突触终末神经递质释放发生障碍,从而影响视觉信号向下一级神经元传导。
2. CSNB组大鼠I-V曲线较SD组右移大约20mV,会导致通道在双极细胞暗适应生理电位范围(-70mV—-20mV)内难以除极化。
3. CSNB大鼠RBCs的突触前GABAA和GABAC受体介导的抑制性突触后电流(IPSCS)消失,提示其触终末神经递质释放过程发生障碍,难以触发来自AⅡACs的负反馈。这种负反馈障碍会影响rod视觉信号局部突触环路放大机制和视觉信号向神经节细胞传导的可塑性。
4.CSNB大鼠胞吐系数EI明显降低,说明CSNB组大鼠RBCs因为钙内流导致递质囊泡和细胞膜融合,使细胞膜表面积(胞吐系数)增加的程度明显弱于SD组大鼠。因此得到关于CSNB组RBCs触终末神经递质囊泡释放发生障碍更为直观的证据。
综上所述,CSNB大鼠双极细胞L-钙通道电生理特征改变会严重影响其向下级神经元释放神经递质,其可能是导致CSNB发病的机制之一。
X-linked congenital stationary night blindness (X-CSNB) is a congenital non-progressive retinal disorder characterized by defective in rod signal system. It can be divided into complete and incomplete form depending on electroretino-gram (ERG) and X-link or autosomal forms depending on genetic mode. The pa-thology mechanism of CSNB is not very clear now and there have no effective therapeutic methods for treatment. Model animal is an essential element for the investigations of hereditary diseases. The spontaneous CSNB model rats devel-oped by our laboratory will improve those investigations as following: the pa-thopoiesis gene of these rats has been identified--Cacna1f gene, so their genetic trait is as X-linked and incomplete form CSNB (XL-iCSNB);electrophysiology and behavioral research demonstrated that they have overcome shortcomings re-flected by genetic engineering model animals, such as obvious discrepancy from clinical circumstance. Therefore they would be a useful model for investigations of CSNB’s pathology mechanism and the circuit of retinal signal transmission.
Bipolar cells (BCs) play a critical role in the process of retinal signal trans-mission, especially in the interaction between retinal rod and cone signal trans-mission path. The L-type calcium channel encoded by Cacna1f gene has been considered as a key point in triggering off neurotransmitter vesicular release of retinal neuron. The dysfunction of L-type calcium channel might cause distur-bances of retinal signal transmission. In order to test the hypothesis, whole-cell patch clamp technique was adopt to investigate the electrophysiological and pharmacological properties of L-type calcium channel of RBCs in iCSNB rats in this study. As the anatomic structure and physiological function of vertebrate re-tina have great resemblances, the research might provide proof for elucidation of CSNB’s pathology mechanism and subsequent invention of effective therapeutic measures.
Methods and material
The CSNB rats identified and breed by our laboratory were adopted in this re-search (4-8weeks old,F20/F21). Wild SD rats as control were provided by La-boratory Animal Center of Fourth Military Medical University. According to the reference, eyeball was extracted from rats which were anesthetized and decapi-tated and 200μm retinal vertical slices were prepared by hand microtome. Under infrared microscope,the RBCs from retinal slices were identified by their special shape and established a tight-seal whole-cell recording configurations for calcium channel currents recording. Resting membrane capacitance (restCm) and the in-crease of restCm(△Cm) after protocol activation(depolarization from -60 mV to 0 mV, time course 200ms) were used to calculate the exocytotic index(EI). L-type calcium channel blocker and GABA-receptor blocking pharmacon PTX were used for observing the pharmacology properties of L-type calcium channel in RBCs. Data were analyzed off-line using pClamp8.1 (Axon, America) and Origin Programs (Microcal software, UK).
Results
1. Inward currents were recorded both in SD and CSNB rat group. The electro-physiology characteristic of these inward currents were consistent with L-type calcium currents’: activated at high depolarize potential; very slow inactivation; channel ion carrier was Ca2+ ----similar currents could not be recorded if Ca2+ was replaced with Mg2+ in the extracellular perfusate.
2. Pharmacology properties of these inward currents : At low concentration (10μm) ,L-type specified calcium channel blocker nifedipine could obviously and effectively block these currents both in SD group and CSNB group. Combining with electrophysiology characteristic of these currents, it might derive the con-clusion that the currents recorded in experiment were L-type calcium currents.
3. The L-type calcium currents in SD group activated at -40mv, and reached their peak amplitude between the -20 and -30mV with an average of -33.2±2.5pA dur-ing ramp depolarizing (n=20); whereas CSNB group activated between the -20 and -30mV, and reached their peak amplitude around the of -15mV with an aver-age of 12.2±2.3pA during ramp depolarizing (n=23).
4. Outwards currents overlaying on calcium current during depolarization at higher degrees (-20 and -30mV) were observed in SD group( n=11) .The ampli-tude of the currents were closely related to the position and depth of RBCs in re-tinal vertical slices, and they could be effectively eliminated by GABA-receptor blocker PTX(100μm). But no similar current was observed in RBCs of CSNB group during depolarization.
5.After 200ms depolarization from -60mv to 0mv, the restCm of both groups increased(△Cm). The EI (Exocytotic index )was calculated based on△Cm. The mean restCm,△Cm and EI were 4146.600±544.202 fF, 29.600±7.472 fF and 0.723±0.199 in SD rat group (n=20) and 4356.957±549.493, 12.348±6.919 and 0.291±0.173 in CSNB group (n=23), respectively. Compared with SD group, the△Cm and EI were significantly lower in CSNB rat group ( p<0.01).
Conclusion
1. L-type calcium channel currents could be recorded both in RBCs of SD and CSNB rat groups. The peak amplitude of L-type calcium channel currents in CSNB rat group is significantly lower than SD rat group. It suggests that the Ca2+ concentration in synapse terminals of RBCs of CSNB rat might be too low to trigger off the neurotransmitter vesicular release at normal velocity and might arise disturbances of retinal signal transmission to third order neurons.
2. The I-V curve shift to right in RBCs of CSNB might deteriorate the depolariza-tion of RBCs at physiology dark adaptation potentials(-70mV to -20mV).
3. Inhibitory postsynaptic currents (IPSCs) could not be recorded in CSNB rat suggests that disruption of neurotransmitter release might cause dysfunction of negative feedback from rod-amacrine cells. This dysfunction of negative feed-back might interrupt the amplification mechanism and flexibility of visual signal transmission circuit.
4. The EI is decreased in RBCs of CSNB rat than SD rat. It may provide more direct proof for the argument of neurotransmitter vesicularr release disruption in CSNB group’s RBCs.
In summary, the alterations of L-type calcium channel property in rod bipolar cell of CSNB led to disruption of neurotransmitter release and visual signal transmission, which might be one of pathophysiological mechanisms for CSNB.
鉴于双极细胞在视觉信号转导,以及视杆与视锥回路间相互作用中起着非常重要的作用,本实验采用利用全细胞膜片钳技术对本实验室培育的CSNB大鼠RBCsL-钙通道电生理学和通道药理学特征进行观察,并探讨其与视网膜视觉信号传递障碍之间的联系。脊椎动物视网膜有非常相似的解剖结构和生理机能,不同动物的实验结果种群变异性很小,因此研究CSNB钙通道电流特征可为进一步明确这种疾病的发病机制及采取针对性的视觉干预保护措施提供依据。
材料与方法
实验采用本实验室鉴定发现,并建立近交系的CSNB大鼠(F20/F21,4～8周龄)及正常同龄对照SD大鼠,深度麻醉后处死大鼠摘取眼球,利用手动切片机制作视网膜切片,在红外干涉显微成像系统中寻找RBCs胞体,运用全细胞膜片钳模式记录L-钙通道电流;给细胞施加阶跃刺激(从-60 mV除极至0mV,时程200ms),记录程序刺激后细胞静息膜电容(restCm)的变化值(△Cm),并据此计算胞吐系数EI( Exocytotic index);分别施加L-钙通道阻断剂nifedipine和GABA受体阻断剂PTX来观察通道的药理学特征;用应用Axon公司的pClamp8.1软件进行数据测量分析,获取RBCsL-钙通道电生理学指标。在Clampfit上选取有代表性的实验记录,导入到Origin软件进行分析和作图。
结果
1. RBCsL-钙通道电流特征
给细胞施加阶跃刺激和斜坡刺激后,在SD组和CSNB组大鼠的RBCs中均可记录出内向电流,其电生理学特征符合L-钙通道电流特点:在较高除极电位激活;失活缓慢;载流离子为Ca2+:用同等浓度Mg2+代替灌流液中的Ca2+,未能记录到类似电流。
2. L-钙通道药理学特性
特异性L-钙通道阻断剂nifedipine(10μm)可以完全阻断SD组和CSNB组所记录的内向电流。结合其电生理学特征我们可以判定本实验在RBCs所记录到的内向电流为L型钙通道电流。
3. SD大鼠与CSNB大鼠RBCs L-钙通道电流比较SD组大鼠RBCs L-钙通道于-40mV左右开放,通道电流于-20和-30mV之间达到峰值:-33.2±2.5pA(n=20)。CSNB组大鼠RBCs L-钙通道于-20mV和-30mV之间开始激活,通道电流于-15mV左右达峰,峰值为12.2±2.3pA(n=23)。
4. SD大鼠视网膜RBCs的负反馈电流
SD组较强程度除极(-20m和-30mv)时可在Ca2+电流上发现较小的外向的电流(n=11),电流大小与细胞在切片中的位置有关,位置越深外向电流越大。应用GABAA和GABAC受体阻断剂PTX(100μm)能够明显阻断这种外向电流,提示其为为RBCs的突触前GABAA和GABAC受体介导的抑制性突触后电流(inhibitory postsynaptic current ,IPSCS)。而在CSNB组所有记录细胞中均未发现此种外向电流。
5.SD大鼠与CSNB大鼠RBCs胞吐指数差异
给细胞施加阶跃刺激(从-60 mV除极至0mV,时程200ms),记录程序刺激后restCm的变化值(△Cm),并据此计算胞吐系数EI:SD组大鼠restCm为:4146.600±544.202 fF,△Cm为29.600±7.472 fF,EI:0.723±0.199;CSNB组大鼠restCm为:4356.957±549.493 ,△Cm为12.348±6.919 , EI为0.291±0.173。SD组大鼠△Cm较CSNB组大鼠高,EI较CSNB组大鼠大,有明显差异(p<0.01)与对照组比较,CSNB大鼠的△Cm和EI明显降低(p<0.01)。
结论
1.实验在CSNB组和SD组大鼠RBCs中所记录的电流为L-钙通电流;CSNB组大鼠RBCs L-钙通电流峰值明显小于SD组大鼠,推测CSNB大鼠电流强度降低导致胞内,尤其是突触终末的Ca2+浓度降低,难以达到触发正常速率神经递质释放所需要的浓度,因此可能会使突触终末神经递质释放发生障碍,从而影响视觉信号向下一级神经元传导。
2. CSNB组大鼠I-V曲线较SD组右移大约20mV,会导致通道在双极细胞暗适应生理电位范围(-70mV—-20mV)内难以除极化。
3. CSNB大鼠RBCs的突触前GABAA和GABAC受体介导的抑制性突触后电流(IPSCS)消失,提示其触终末神经递质释放过程发生障碍,难以触发来自AⅡACs的负反馈。这种负反馈障碍会影响rod视觉信号局部突触环路放大机制和视觉信号向神经节细胞传导的可塑性。
4.CSNB大鼠胞吐系数EI明显降低,说明CSNB组大鼠RBCs因为钙内流导致递质囊泡和细胞膜融合,使细胞膜表面积(胞吐系数)增加的程度明显弱于SD组大鼠。因此得到关于CSNB组RBCs触终末神经递质囊泡释放发生障碍更为直观的证据。
综上所述,CSNB大鼠双极细胞L-钙通道电生理特征改变会严重影响其向下级神经元释放神经递质,其可能是导致CSNB发病的机制之一。
X-linked congenital stationary night blindness (X-CSNB) is a congenital non-progressive retinal disorder characterized by defective in rod signal system. It can be divided into complete and incomplete form depending on electroretino-gram (ERG) and X-link or autosomal forms depending on genetic mode. The pa-thology mechanism of CSNB is not very clear now and there have no effective therapeutic methods for treatment. Model animal is an essential element for the investigations of hereditary diseases. The spontaneous CSNB model rats devel-oped by our laboratory will improve those investigations as following: the pa-thopoiesis gene of these rats has been identified--Cacna1f gene, so their genetic trait is as X-linked and incomplete form CSNB (XL-iCSNB);electrophysiology and behavioral research demonstrated that they have overcome shortcomings re-flected by genetic engineering model animals, such as obvious discrepancy from clinical circumstance. Therefore they would be a useful model for investigations of CSNB’s pathology mechanism and the circuit of retinal signal transmission.
Bipolar cells (BCs) play a critical role in the process of retinal signal trans-mission, especially in the interaction between retinal rod and cone signal trans-mission path. The L-type calcium channel encoded by Cacna1f gene has been considered as a key point in triggering off neurotransmitter vesicular release of retinal neuron. The dysfunction of L-type calcium channel might cause distur-bances of retinal signal transmission. In order to test the hypothesis, whole-cell patch clamp technique was adopt to investigate the electrophysiological and pharmacological properties of L-type calcium channel of RBCs in iCSNB rats in this study. As the anatomic structure and physiological function of vertebrate re-tina have great resemblances, the research might provide proof for elucidation of CSNB’s pathology mechanism and subsequent invention of effective therapeutic measures.
Methods and material
The CSNB rats identified and breed by our laboratory were adopted in this re-search (4-8weeks old,F20/F21). Wild SD rats as control were provided by La-boratory Animal Center of Fourth Military Medical University. According to the reference, eyeball was extracted from rats which were anesthetized and decapi-tated and 200μm retinal vertical slices were prepared by hand microtome. Under infrared microscope,the RBCs from retinal slices were identified by their special shape and established a tight-seal whole-cell recording configurations for calcium channel currents recording. Resting membrane capacitance (restCm) and the in-crease of restCm(△Cm) after protocol activation(depolarization from -60 mV to 0 mV, time course 200ms) were used to calculate the exocytotic index(EI). L-type calcium channel blocker and GABA-receptor blocking pharmacon PTX were used for observing the pharmacology properties of L-type calcium channel in RBCs. Data were analyzed off-line using pClamp8.1 (Axon, America) and Origin Programs (Microcal software, UK).
Results
1. Inward currents were recorded both in SD and CSNB rat group. The electro-physiology characteristic of these inward currents were consistent with L-type calcium currents’: activated at high depolarize potential; very slow inactivation; channel ion carrier was Ca2+ ----similar currents could not be recorded if Ca2+ was replaced with Mg2+ in the extracellular perfusate.
2. Pharmacology properties of these inward currents : At low concentration (10μm) ,L-type specified calcium channel blocker nifedipine could obviously and effectively block these currents both in SD group and CSNB group. Combining with electrophysiology characteristic of these currents, it might derive the con-clusion that the currents recorded in experiment were L-type calcium currents.
3. The L-type calcium currents in SD group activated at -40mv, and reached their peak amplitude between the -20 and -30mV with an average of -33.2±2.5pA dur-ing ramp depolarizing (n=20); whereas CSNB group activated between the -20 and -30mV, and reached their peak amplitude around the of -15mV with an aver-age of 12.2±2.3pA during ramp depolarizing (n=23).
4. Outwards currents overlaying on calcium current during depolarization at higher degrees (-20 and -30mV) were observed in SD group( n=11) .The ampli-tude of the currents were closely related to the position and depth of RBCs in re-tinal vertical slices, and they could be effectively eliminated by GABA-receptor blocker PTX(100μm). But no similar current was observed in RBCs of CSNB group during depolarization.
5.After 200ms depolarization from -60mv to 0mv, the restCm of both groups increased(△Cm). The EI (Exocytotic index )was calculated based on△Cm. The mean restCm,△Cm and EI were 4146.600±544.202 fF, 29.600±7.472 fF and 0.723±0.199 in SD rat group (n=20) and 4356.957±549.493, 12.348±6.919 and 0.291±0.173 in CSNB group (n=23), respectively. Compared with SD group, the△Cm and EI were significantly lower in CSNB rat group ( p<0.01).
Conclusion
1. L-type calcium channel currents could be recorded both in RBCs of SD and CSNB rat groups. The peak amplitude of L-type calcium channel currents in CSNB rat group is significantly lower than SD rat group. It suggests that the Ca2+ concentration in synapse terminals of RBCs of CSNB rat might be too low to trigger off the neurotransmitter vesicular release at normal velocity and might arise disturbances of retinal signal transmission to third order neurons.
2. The I-V curve shift to right in RBCs of CSNB might deteriorate the depolariza-tion of RBCs at physiology dark adaptation potentials(-70mV to -20mV).
3. Inhibitory postsynaptic currents (IPSCs) could not be recorded in CSNB rat suggests that disruption of neurotransmitter release might cause dysfunction of negative feedback from rod-amacrine cells. This dysfunction of negative feed-back might interrupt the amplification mechanism and flexibility of visual signal transmission circuit.
4. The EI is decreased in RBCs of CSNB rat than SD rat. It may provide more direct proof for the argument of neurotransmitter vesicularr release disruption in CSNB group’s RBCs.
In summary, the alterations of L-type calcium channel property in rod bipolar cell of CSNB led to disruption of neurotransmitter release and visual signal transmission, which might be one of pathophysiological mechanisms for CSNB.
引文
1. Boycott KM, Maybaum TA, Naylor MJ, Weleber RG, Robitaille J, Miyake Y, Bergen AA, Pierpont ME, Pearce WG, Bech-Hansen NT. A summary of 20 CACNA1F mutations identified in 36 families with incomplete X-linked congenital stationary night blindness, and characterization of splice variants. Hum Genet, 2001; 108(2) : 91-7
2. Hemara-Wahanui A, Berjukow S, Hope CI, Dearden PK, Wu SB, Wil-son-Wheeler J, Sharp DM, Lundon-Treweek P, Clover GM, Hoda JC, Striessnig J, Marksteiner R, Hering S, Maw MA. A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation . PNAS, 2005; 102(21): 7553-8
3. Mansergh F, Orton NC, Vessey JP, Lalonde MR, Stell WK, Tremblay F, Barnes S, Rancourt DE, Bech-Hansen NT. Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Human Molecular Genetics, 2005; 14( 20): 3035-46
4. Zhang Z, Gu Y, Li L, Long T, Guo Q, Shi L. A potential spontaneous rat model of X-linked congenital stationary night blindness. Doc Ophthalmol, 2003; 107(1): 53-7
5. Gu Y, Wang L, Zhou J, Guo Q, Liu N, Ding Z, Li L, Liu X, An J, Yan G, Yao L, Zhang Z.A naturally-occurring mutation in Cacna1f in a rat model of congenital stationary night blindness. Molecular Vision , 2008; 14(1): 20-8
6. Leo MC, Emine G. Development of On and Off retinal pathways and retino-geniculate projections.Progress in Retinal and Eye Research , 2004; 23(1): 31-51
7. Nettleship E. A history of congenital stationary night-blindness in nine con-secutive generations. Trans Ophthal Soc UK, 1907; 27: 269-93
8. Weleber RG, Tongue AC. Congenital stationary night blindness presenting as Leber's congenital amaurosis. Arch Ophthalmol, 1987; 105(3): 360-5
9.李序,刘晓玲.性静止性夜盲研究进展.医学眼科学分册, 2004; 8(6):396-400
10. Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T. Congenital sta-tionary night blindness with negative electroretinogram: a new classification. Arch Ophthal, 1986; 104(7): 1013-20
11.庄树林,胡松年,邹建卫,商志才,俞庆森.先天性静止性夜盲的分子遗传学研究进展.国外医学遗传学分册, 2004; 27(1): 43-5
12. Gal A, Xu S, Piczenik Y, Eiberg H, Duvigneau C, Schwinger E, Rosenberg T. Gene for autosomal dominant congenital stationary night blindness maps to the same region as the gene for the beta-subunit of the rod photoreceptor cGMP phosphodiesterase (PDEB) in chromosome 4p16.3. Hum Mol Genet, 1994; 3(2): 323-5
13. Gal A, Orth U, Baehr W, Schwinger E, Rosenberg T. Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness. Nat Genet, 1994; 7(1): 64-8
14. Dryja TP, Berson EL, Rao VR, Oprian DD. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet, 1993; 4(3): 280-3
15. al-Jandal N, Farrar GJ, Kiang AS, Humphries MM, Bannon N, Findlay JB, Humphries P, Kenna PF. A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blind-ness. Hum Mutat, 1999; 13(1): 75-81
16. Dryja TP, Hahn LB, Reboul T, Arnaud B. Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of conge-nital stationary night blindness. Nature Genet, 1996; 13(3): 358-65
17. Yamamoto S, Sippel KC, Berson EL, Dryja TP. Defects in the rhodopsin ki-nase gene in the Oguchi form of stationary night blindness. Nature Genet, 1997; 15(2): 175-8
18. Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, Derlacki DJ, Rajagopalan AS. Night blindness and abnormal cone elec-troretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci USA, 2005; 102(13): 4884-9
19. Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP. Muta-tions in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nature Genet, 1999; 22(2): 188-91
20. Saga M, Mashima Y, Kudoh J, Oguchi Y, Shimizu N. Gene analysis and evaluation of the single founder effect in Japanese patients with Oguchi dis-ease. Jpn J Ophthalmol, 2004; 48(4): 350-2
21. Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AAB, Prinsen CFM, Polomeno RC, Gal A, Drack AV, Musa-rella MA, Jacobson SG, Young RSL, Weleber RG. Mutations in NYX, en-coding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nature Genet, 2000; 26(3): 319-23
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2. Hemara-Wahanui A, Berjukow S, Hope CI, Dearden PK, Wu SB, Wil-son-Wheeler J, Sharp DM, Lundon-Treweek P, Clover GM, Hoda JC, Striessnig J, Marksteiner R, Hering S, Maw MA. A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation . PNAS, 2005; 102(21): 7553-8
3. Mansergh F, Orton NC, Vessey JP, Lalonde MR, Stell WK, Tremblay F, Barnes S, Rancourt DE, Bech-Hansen NT. Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Human Molecular Genetics, 2005; 14( 20): 3035-46
4. Zhang Z, Gu Y, Li L, Long T, Guo Q, Shi L. A potential spontaneous rat model of X-linked congenital stationary night blindness. Doc Ophthalmol, 2003; 107(1): 53-7
5. Gu Y, Wang L, Zhou J, Guo Q, Liu N, Ding Z, Li L, Liu X, An J, Yan G, Yao L, Zhang Z.A naturally-occurring mutation in Cacna1f in a rat model of congenital stationary night blindness. Molecular Vision , 2008; 14(1): 20-8
6. Leo MC, Emine G. Development of On and Off retinal pathways and retino-geniculate projections.Progress in Retinal and Eye Research , 2004; 23(1): 31-51
7. Nettleship E. A history of congenital stationary night-blindness in nine con-secutive generations. Trans Ophthal Soc UK, 1907; 27: 269-93
8. Weleber RG, Tongue AC. Congenital stationary night blindness presenting as Leber's congenital amaurosis. Arch Ophthalmol, 1987; 105(3): 360-5
9.李序,刘晓玲.性静止性夜盲研究进展.医学眼科学分册, 2004; 8(6):396-400
10. Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T. Congenital sta-tionary night blindness with negative electroretinogram: a new classification. Arch Ophthal, 1986; 104(7): 1013-20
11.庄树林,胡松年,邹建卫,商志才,俞庆森.先天性静止性夜盲的分子遗传学研究进展.国外医学遗传学分册, 2004; 27(1): 43-5
12. Gal A, Xu S, Piczenik Y, Eiberg H, Duvigneau C, Schwinger E, Rosenberg T. Gene for autosomal dominant congenital stationary night blindness maps to the same region as the gene for the beta-subunit of the rod photoreceptor cGMP phosphodiesterase (PDEB) in chromosome 4p16.3. Hum Mol Genet, 1994; 3(2): 323-5
13. Gal A, Orth U, Baehr W, Schwinger E, Rosenberg T. Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness. Nat Genet, 1994; 7(1): 64-8
14. Dryja TP, Berson EL, Rao VR, Oprian DD. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet, 1993; 4(3): 280-3
15. al-Jandal N, Farrar GJ, Kiang AS, Humphries MM, Bannon N, Findlay JB, Humphries P, Kenna PF. A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blind-ness. Hum Mutat, 1999; 13(1): 75-81
16. Dryja TP, Hahn LB, Reboul T, Arnaud B. Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of conge-nital stationary night blindness. Nature Genet, 1996; 13(3): 358-65
17. Yamamoto S, Sippel KC, Berson EL, Dryja TP. Defects in the rhodopsin ki-nase gene in the Oguchi form of stationary night blindness. Nature Genet, 1997; 15(2): 175-8
18. Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, Derlacki DJ, Rajagopalan AS. Night blindness and abnormal cone elec-troretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci USA, 2005; 102(13): 4884-9
19. Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP. Muta-tions in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nature Genet, 1999; 22(2): 188-91
20. Saga M, Mashima Y, Kudoh J, Oguchi Y, Shimizu N. Gene analysis and evaluation of the single founder effect in Japanese patients with Oguchi dis-ease. Jpn J Ophthalmol, 2004; 48(4): 350-2
21. Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AAB, Prinsen CFM, Polomeno RC, Gal A, Drack AV, Musa-rella MA, Jacobson SG, Young RSL, Weleber RG. Mutations in NYX, en-coding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nature Genet, 2000; 26(3): 319-23
22. Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, We-ber BHF, Wutz K, Gutwillinger N, Ruther K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, Meindl A. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nature Genet, 1998; 19(3): 260-3
23. Humphries MM, Rancourt D, Farrar GJ, Kenna P, Hazel M, Bush RA, Siev-ing PA, Sheils DM, McNally N, Creighton P, Erven A, Boros A, Gulya K, Capecchi MR, Humphries P. Retinopathy induced in mice by targeted dis-ruption of the rhodopsin gene. Nat Genet, 1997; 15(2): 216-19
24. Lem J, Krasnoperova NV, Calvert PD, Kosaras B, Cameron DA, Nicolo M, Makino CL, Sidman RL. Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc Natl Acad Sci USA, 1999; 96(2): 736-41
25. Driessen CA, Winkens HJ, Hoffmann K, Kuhlmann LD, Janssen BP, Van Vugt AH, Van Hooser JP, Wieringa BE, Deutman AF, Palczewski K, Rueth-er K, Janssen JJ. Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cis-retinols and cis-retinyl esters. Mol Cell Biol, 2000; 20(12): 4275-87
26. Pardue MT, McCall MA, LaVail MM, Gregg RG, Peachey NS. A naturally occurring mouse model of X-linked congenital stationary night blindness. Invest Ophthalmol Vis Sci, 1998; 39(12): 2443-49
27. Gregg RG, Mukhopadhyay S, Candille SI, Ball SL, Pardue MT, McCall MA, Peachey NS. Identification of the gene and the mutation responsible for the mouse nob phenotype. Invest Ophthalmol Vis Sci, 2003; 44(1): 378-84
28. Wu J, Peachey NS, Marmorstein AD. Light-evoked responses of the mouse retinal pigment epithelium. J Neurophysiol, 2004; 91(3): 1134-42
29. Racine J, Behn D, Simard E, Lachapelle P. Spontaneous occurrence of a po-tentially night blinding disorder in guinea pigs. Doc Ophthalmol, 2003; 107(1): 59-69
30. Narfstrom K, Wrigstad A, Nilsson SE. The Briard dog: a new animal model of congenital stationary night blindness. Br J Ophthalmol, 1989; 73(9): 750-6
31. Gu YH,Zhang ZM,Long T, Li L, Hou BK, Guo Q. A naturally occurring rat model of X-linked cone dysfunction. Invest Ophthalmol Vis Sci,2003; 44(12):5321-6
32. Daw NW. Visual Development . Plenum, New York, 1995; 242 p, chap 9
33. Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF. Local GABA Circuit Control of Experience-Dependent Plasticity in Devel-oping Visual Cortex. Science, 1998; 282(5393): 1504-8
34. Michaelides M, Hardcastle AJ, Hunt DM,Moore AT. Progressive cone-rod dystrophies:phenotypes and underlying molecular genetic basis. Surv Oph-thalmol, 2006; 51(3):232-58
35. Ripps H. Cell death in retinitis pigmenttosa: gap junctions and the "bystand-er"effect. Exp Eye Res, 2002; 72(3): 327-36
36. Banin E, Cideciyan AV, Alemán Ts, Petters RM, Wong F, Milam AH, Ja-cobson SG. Retinal rod photoreceptor-specific gene mutiation perturbs cone pathway development.Neuron, 1999; 23(3): 549-57
37. Hess P. Calcium channel in vertebrate cells. Annu Rev Neurosci ,1990; 13: 337-56.
38. Mccleskey EW. Calcium channels: cellular roles and molecular mechanisms. Curr Opin Neurobio, 1994; 4(3): 304-12
39. Byerly AD, Grinnell D, Armstrong M, Jackson B, Plenum Hagiwara. Cal-cium channel diversity in calcium and ion channel modution. NewYork 1988; 3-18
40. McRory JE, Hamid J, Doering CJ, Garcia E, Parker R, Hamming K, Chen L, Hildebrand M, Beedle AM, Feldcamp L, Zamponi GW, Snutch TP. The CACNA1F Gene Encodes an L-Type Calcium Channel with Unique Bio-physical Properties and Tissue Distribution. The Journal of Neuroscience,2004 ; 24(7): 1707-18
41. Canerall WA, Striessnig J, Snutch TP. Compendium of Voltage-Gated Ion Channels:Calcium Channels. Pharmacol Rev, 2003; 55(4): 579-81
42. Bourinet E,Mangoni ME, Nargeot J. Dissecting the functional role of differ-ent isoforms of the L-type Ca2+ channel. J Clin Invest, 2004; 113(10): 1382-4
43. Hogan K, Greg RG, Powers PA. Structure and alternative splicing of the gene encoding the human beta1 subunit of voltage dependent calcium chan-nels. Neurosci Lett, 1999; 277(2):111-4
44. Gurnett CA, Campbell KP. Transmembrane auxiliary sybunits of vol-tage-dependent ion channels. J B iol Chem, 1996; 271(45): 27975-8
45. Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol, 2000, 16: 521-55
46. Ertel EA, Campbell KP, Harpold MM, Horfmann F, Mori Y, Perez-Reyes E, Schwartz A, Snutch TP, Tanabe T, Birnbaumer L. Nomenclature of vol-tage-gated calcium channels.Neuron, 2000; 25(3): 533-5
47.于耀清,陈军.电压门控性钾、钙、钠离子通道的结构和分类.中华神经医学杂志. 2005; 5(4):515-20
48. Naylor MJ, Rancourt DE, Bech-Hansen NT. Isolation and characterization of a calcium channel gene, Cacna1f, the murine orthologue of the gene for in-complete X-linked congenital stationary night blindness. Genomics, 2000; 66(3): 324-7
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