Dopaminergic Modulation of Dendritic Excitability

树突兴奋性的多巴胺能调节

• 批准号: 6921477
• 负责人: SRDJAN D ANTIC
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-10 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921477
• 关键词: AMPA receptors; NMDA receptors; action potentials; brain electrical activity; brain metabolism; calcium flux; calcium indicator; charge coupled device camera; dendrites; dopamine; dopamine receptor; glutamate receptor; glutamates; laboratory rat; neural information processing; neural transmission; neurotransmitter metabolism; neurotransmitter transport; prefrontal lobe /cortex; pyramidal cells; schizophrenia; single cell analysis; sodium; synapses; video microscopy

DESCRIPTION (provided by applicant): Schizophrenia is a mental disorder with devastating symptoms, yet, at the macroscopic level, the brains of schizophrenics are no different than the brains of healthy subjects. Recent electron microscope studies, however, revealed microscopic structural abnormalities that affect the dendrites of neocortical pyramidal neurons. Interestingly, distal parts of these dendrites of pyramidal cells are targets of dopaminergic axon terminals. Furthermore, in prefrontal cortex, an area implicated in pathophysiology of schizophrenia, individual dendritic spines are occupied by two presynaptic terminals; one axon terminal that secretes excitatory transmitter (glutamate), and the other one that secretes dopamine. It is thought that dopamine secretion is elevated in schizophrenia because dopamine receptor blockers alleviate some symptoms. Our working hypothesis is that abnormally high dopamine secretion suppresses dendritic excitability and severely disrupts information processing at the level of individual neurons (a process also know as integration of synaptic inputs). In the laboratory, we are mimicking the arrival of glutamatergic and dopaminergic inputs by delivering glutamate and dopamine pulses locally, onto individual dendritic branches (local application of neurotransmitters through glass pipettes). This approach allows precise control of the location of excitatory input to the dendritic tree, with precise timing, and most importantly, the role of presynaptic mechanisms in the interpretation of experimental results is eliminated. With the help of voltage-sensitive dyes, the effects of dopamine on dendritic membrane potential will be analyzed simultaneously at the glutamate stimulation site, as well as in the neighboring dendrites that are exposed to neither glutamate nor dopamine. The proposed experiments are expected to yield a more complete picture of how local fluctuation in dopamine level can shape the information processing in individual neurons, and provide impetus for new therapeutic approaches in schizophrenia.

描述（由申请人提供）：精神分裂症是一种具有毁灭性症状的精神障碍，但是，在宏观层面上，精神分裂症患者的大脑与健康受试者的大脑没有什么不同。然而，最近的电子显微镜研究揭示了影响新皮层金字塔神经元树突的显微镜结构异常。有趣的是，这些锥体细胞的树突的远端部分是多巴胺能轴突末端的靶标。此外，在前额叶皮层中，该区域与精神分裂症的病理生理学有关，单个树突状棘被两个突触前末端占据。一个分泌兴奋性发射器（谷氨酸）的轴突末端，另一个分泌多巴胺的轴突末端。人们认为，在精神分裂症中，多巴胺分泌升高，因为多巴胺受体阻滞剂可以减轻某些症状。我们的工作假设是，异常高的多巴胺分泌抑制了树突兴奋性，并严重破坏了单个神经元级别的信息处理（这一过程也称为突触输入的整合）。在实验室中，我们通过将谷氨酸和多巴胺脉冲在局部将谷氨酸和多巴胺能输入的到来模仿（通过玻璃移液器局部应用神经递质的局部应用）。这种方法允许精确控制对树突树的兴奋性输入的位置，并具有精确的时机，最重要的是，突触前机制在解释实验结果中的作用被消除了。借助对电压敏感的染料，将在谷氨酸刺激部位以及既不暴露于谷氨酸和多巴胺的邻近树突中同时分析多巴胺对树突状膜电位的影响。预计所提出的实验将对多巴胺水平的局部波动如何影响单个神经元中的信息处理，并为精神分裂症的新治疗方法提供动力。