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.

项目总结 许多神经细胞类型通过电突触相互通信，这允许 电流和离子通过称为缝隙连接的通道。电突触在FAST中起着不可或缺的作用 感觉运动过程中的交流，以及大脑多个区域的同步交流。 虽然快速和同步的沟通对于许多中枢和外周大脑功能是必要的，但 缝隙结调制背后的机制仍未得到充分研究。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反应 蛋白质，它改变了这些通道的开放概率。然而，神经胶质细胞在调节中的作用 关于电突触通讯的问题，以前还没有解决过。化学突触的调制 在神经胶质细胞领域中，通过神经胶质传递或神经胶质细胞释放分子进行的通讯研究得很好。 生物学。该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。 视网膜中光适应回路的神经元具有促进激活 视光强而定的杆状或锥状路径。一个这样的神经元，AII无长突细胞， 通过开放和关闭电子突触之间的缝隙连接来促进这一机制 其他AII细胞和锥体双极细胞。该项目的目标是确定Müler神经胶质细胞是否在 在这种瞬间的可塑性中。Müler胶质细胞是视网膜的主要星形胶质细胞，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在AII中调节缝隙连接 电子突触。腺苷是一个令人感兴趣的目标，因为腺苷水平在黑暗中增加。目标2将 确定刺激或抑制Müler神经胶质细胞是否调节所有电突触的缝隙连接。米勒小室 GQ DREADD的CNO激活将刺激神经胶质细胞的传递，GQ DREADD将靶向于Müller细胞 GLAST启动子控制下的病毒载体。Müler细胞抑制对ALI电活动的影响 突触将使用IP3R2KO小鼠模型进行评估。腺苷的药理拮抗作用 受体将揭示腺苷是否介导了这些电子突触的Müler神经胶质调制。的程度 调制将通过使用双全细胞膜片钳的电导测量来确定 电生理学和神经生物素追踪。对神经胶质细胞对电突触的调制的理解是 对于阐明视网膜以及其他系统中的电突触功能至关重要，在健康和 疾病。