Glial Modulation of Electrical Synapses in the Retina

视网膜电突触的神经胶质调节

• 批准号: 10589506
• 负责人: Chloe E Cable
• 金额: $ 3.39万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-31 至 2023-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589506
• 关键词: Address; Adenosine; Affect; Amacrine Cells; Area; Astrocytes; Bathing; Biology; Brain; Calcium Signaling; Cell physiology; Cells; Chemical Synapse; Circadian Rhythms; Clozapine; Communication; Cone; Connexins; Coupled; Coupling; Dark Adaptation; Darkness; Designer Drugs; Disease; Electrical Synapse; Electrophysiology (science); Epilepsy; Event; Extracellular Space; GLAST Protein; Gap Junctions; Genetic; Giant Cells; Goals; Health; Impairment; Inner Plexiform Layer; Ions; Knowledge; Lead; Light; Light Adaptations; Measurement; Measures; Mediating; Methods; Modeling; Muller' s cell; Mus; Nervous system structure; Neuraxis; Neuroglia; Neuromodulator; Neurons; Neurotransmitters; Oxides; Pathology; Pathway interactions; Peripheral; Pharmacology; Phosphorylation; Photoreceptors; Physiological; Play; Population; Probability; Process; Protein Dephosphorylation; Purinergic P1 Receptors; Research; Rest; Retina; Retinal Degeneration; Retinal Diseases; Rod; Role; Schizophrenia; Second Messenger Systems; Shapes; Signal Transduction; Slice; Specificity; System; Testing; Tracer; Vertebrate Photoreceptors; Viral Vector; adeno-associated viral vector; antagonist; cell type; experimental study; information processing; interest; mouse model; neural circuit; neurobiotin; neuroregulation; novel; patch clamp; promoter; receptor; response; synaptic function; transmission process; visual processing; voltage clamp

PROJECT SUMMARY Many neuronal cell types communicate with one another via electrical synapses, which allow the flow of current and ions through channels called gap junctions. Electrical synapses play an integral role in fast communication within sensorimotor processes, and in synchronous communication in many brain areas. Though fast and synchronous communication is necessary for many central and peripheral brain functions, the mechanisms behind gap junction modulation remain understudied. Studies in the retina have explored neuromodulators and signaling cascades that lead to phosphorylation or dephosphorylation of gap junction proteins, which alters the open probability of these channels. However, the role of glial cells in the modulation of electrical synapse communication has not been previously addressed. Modulation of chemical synapse communication by gliotransmission, or the release of molecules by glia, is well studied in the field of glial biology. This project aims to determine if gliotransmission affects electrical synapse plasticity within the retina. Neurons of the light adaptation circuitry in the retina have mechanisms to facilitate the activation of either the rod or cone pathways depending on ambient light levels. One such neuron, the AII amacrine cell, facilitates this mechanism through the opening and closing of gap junctions at electrical synapses between other AII cells and ON cone bipolar cells. The goal of this project is to determine if Müller glial cells play a role in this transient plasticity. Müller glia are the principal astroglia of the retina which release gliotransmitters in response to retinal activity. Aim 1 will determine if the gliotransmitter adenosine modulates gap junctions at AII electrical synapses. Adenosine is a target of interest because adenosine levels increase in darkness. Aim 2 will determine if stimulation or inhibition of Müller glia modulate gap junctions at AII electrical synapses. Müller cell gliotransmission will be stimulated by CNO activation of Gq DREADDs, which will be targeted to Müller cells with a viral vector under control of the GLAST promoter. The effect of Müller cell inhibition on AII electrical synapses will be assessed using an IP3R2KO mouse model. Pharmacological antagonism of adenosine receptors will reveal if adenosine mediates Müller glial modulation of these electrical synapses. The degree of modulation will be determined using conductance measurements with dual whole-cell patch clamp electrophysiology and neurobiotin tracing. The understanding of glial modulation of electrical synapses is essential for clarifying electrical synapse function in the retina, as well as other systems, in health and disease.

项目摘要 许多神经元细胞类型通过电突触彼此通信，电突触允许神经元的流动。 电流和离子通过缝隙连接通道。电突触在快速反应中起着重要作用， 在感觉运动过程中的交流，以及在许多大脑区域的同步交流。 尽管快速和同步的交流对许多中枢和外周脑功能是必要的， 间隙连接调制背后的机制仍然研究不足。对视网膜的研究探索了 导致缝隙连接磷酸化或去磷酸化的神经调节剂和信号级联 蛋白质，这改变了这些通道的开放概率。然而，神经胶质细胞在调节 电突触通信的原理以前没有被解决过。化学突触的调节 通过神经胶质传递的通讯，或神经胶质释放分子，在神经胶质细胞领域得到了很好的研究。 生物学这个项目旨在确定胶质传递是否影响视网膜内的电突触可塑性。 视网膜中的光适应回路的神经元具有促进光适应回路的激活的机制。 视环境光水平而定的视杆或视锥路径。其中一个神经元，AII无长突细胞， 通过在电突触处的间隙连接的打开和关闭促进这种机制， 其他AII细胞和ON锥双极细胞。该项目的目标是确定Müller胶质细胞是否在 在这种短暂的可塑性中。Müller胶质细胞是视网膜的主要星形胶质细胞，其在视网膜中释放胶质递质。 对视网膜活动的反应。目标1将确定胶质递质腺苷是否调节AII处的缝隙连接 电突触腺苷是感兴趣的目标，因为腺苷水平在黑暗中增加。目标2将 确定刺激或抑制Müller胶质细胞是否调节AII电突触处的间隙连接。米勒细胞 胶质传递将通过Gq DREADD的CNO激活来刺激，Gq DREADD将靶向Müller细胞 用在GLAST启动子控制下的病毒载体。Müller细胞抑制对AII电活动的影响 将使用IP3R2KO小鼠模型评估突触。腺苷的药理拮抗作用 受体将揭示腺苷是否介导这些电突触的Müller神经胶质调制。程度 将使用双全细胞膜片钳的电导测量来确定调制 电生理学和神经生物素示踪。对神经胶质细胞调节电突触的理解是 对于阐明视网膜以及其他系统中的电突触功能至关重要， 疾病