ROD AND CONE SIGNALING PATHWAYS IN MAMMALIAN RETINA

哺乳动物视网膜中的视杆细胞和视锥细胞信号通路

• 批准号: 8207285
• 负责人: Samuel M Wu
• 金额: $ 36.84万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207285
• 关键词: Amacrine Cells; Biological Models; Brain; Cations; Cells; Chloride Ion; Chlorides; Color; Coupling; Defect; Dyes; Eye; Eye diseases; Functional disorder; Glaucoma; Glutamates; Human; Image; Leber' s disease; Light; Macular degeneration; Mediating; Mus; Mutant Strains Mice; Night Blindness; Output; Pathogenesis; Pathway interactions; Process; Relative (related person); Research; Research Project Grants; Research Proposals; Retina; Retinal; Retinal Cone; Salamander; Signal Pathway; Signal Transduction; Site; Snow; Synapses; Techniques; Testing; The Sun; Tigers; Vertebrate Photoreceptors; Vision Disorders; Visual Perception; abstracting; computerized data processing; ganglion cell; light intensity; neural circuit; operation; response; retinal neuron; retinal rods; voltage clamp

PROJECT SUMMARY/ABSTRACT The overall objective of this new research project is to understand detailed synaptic mechanisms underlying rod and cone signaling pathways in the mammalian retina. Anatomical studies have suggested that rod and cone channels in the mammalian retina follow a specific set of circuitry rules: rods make synapses only on rod depolarizing bipolar cells (DBCRs), and DBCRs do not make output synapses directly on ganglion cells (GCs), but indirectly through AII amacrine cells (AIIACs). AIIACs send rod-mediated signals to ON and OFF GCs by "piggybacking" on the cone depolarizing and hyperpolarizing bipolar cells (DBCCs and HBCCs), which synapse on ON and OFF GCs, respectively. In this research proposal, we plan to systematically investigate these mammalian-specific synaptic circuits by using the mouse retina as a model system. In addition to using whole-cell voltage clamp (with dye-filling), anatomical and pharmacological techniques, we will take advantage of four strains of pathway-specific mutant mice to elucidate how mammalian rod and cone signals are transmitted to BCs, ACs and GCs, and to determine whether the mammalian-specific circuitry rules are totally valid, as recent evidence and our preliminary results suggest that the strict rod/cone input rules may not hold for all mammalian retinal neurons. We will test the overall hypothesis that "subpopulations of mouse DBCRs receive direct synaptic inputs from cones and subpopulations of mouse DBCCs and HBCCs receive direct synaptic inputs from rods, the rod- and cone-mediated signals are further mixed by AIIACs before sending to GCs, and the AC-mediated inhibitory synaptic inputs to BCs and GCs carry mixed rod/cone signals". This application has 3 specific aims focused on studying rod and cone contributions to light-evoked cation and chloride currents (¿IC and ¿ICl, representing glutamatergic and GABAergic/glycinergic synaptic inputs, respectively) in: (1) seven types of bipolar cells (HBCMC/Rs, HBCMCs, HBCSCs, DBCC2/MCs, DBCC1/MC/Rs, DBCR2s, DBCR1s); (2) AII amacrine cells; and (3) three types of alpha ganglion cells (ON, sOFF and tOFF ¿GCs) in the dark-adapted mouse retina. Results obtained will increase our understanding of how parallel channels, such as the rod/cone signaling pathways, process, segregate and integrate information in the eye and in the brain. Since many visual disorders are associated with abnormalities in the rod and cone signaling pathways, this research project will help to identify cellular and synaptic sites responsible for the pathogenesis of these eye diseases.

项目摘要/摘要 这一新研究项目的总体目标是了解视杆细胞的详细突触机制。 以及哺乳动物视网膜中的视锥信号通路。解剖学研究表明，杆状和锥状通道 哺乳动物的视网膜遵循一套特定的电路规则：视杆只在视杆上形成突触，使双极细胞去极化。 (DBCRs)，DBCRs并不直接在神经节细胞(GC)上产生输出突触，而是间接通过AII无长突 细胞(AIIAC)。AIIAC通过“搭载”在锥体上去极化和去极化向开和关GC发送杆介导的信号 超极化双极细胞(DBCC和HBCC)，分别在ON和OFF GC上突触。 在这个研究方案中，我们计划通过以下方式系统地研究这些哺乳动物特有的突触电路 以小鼠视网膜为模型系统。除了使用全细胞电压钳(带有染料填充)外，解剖和 药理学技术，我们将利用四个品系的途径特异性突变小鼠来阐明 哺乳动物的视杆细胞和视锥细胞信号被传递到BCS、ACS和GC，并确定哺乳动物特有的 电路规则是完全有效的，因为最近的证据和我们的初步结果表明，严格的棒/锥输入规则 可能并不适用于所有哺乳动物的视网膜神经元。我们将检验总体假设，即“小鼠DBCR的亚群 接受来自锥体和小鼠DBCC亚群的直接突触输入，HBCC接受直接突触输入 从杆状细胞，杆和锥体介导的信号进一步被AIIAC混合，然后发送到GC，AC介导的信号 BCS和GC的抑制性突触输入携带混合的视杆/视锥细胞信号“。 这项应用有三个特定的目标，重点研究杆状和锥体对光诱发阳离子的贡献和 氯电流(IC和ICL，分别代表谷氨酸能和GABA能/甘氨酸能突触输入)： (1)七种双极细胞(HBCMC/Rs、HBCMCs、HBCSCs、DBCC2/MCs、DBCC1/MC/Rs、DBCR2s、DBCR1s)； 无长突细胞；以及(3)暗适应小鼠视网膜中三种类型的阿尔法神经节细胞(ON、SOIF和TOOFF？GCs)。 所获得的结果将增加我们对平行通道，如杆/锥信号通路， 处理、分离和整合眼睛和大脑中的信息。由于许多视力障碍与 视杆细胞和视锥细胞信号通路的异常，这项研究项目将有助于识别细胞和突触位置 对这些眼病的发病机制负有责任。