Dopaminergic Modulation of Dendritic Excitability

描述(申请人提供)：精神分裂症是一种具有破坏性症状的精神障碍，但在宏观层面上，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质锥体神经元树突的微观结构异常。有趣的是，这些锥体细胞树突的远端部分是多巴胺能轴突终末的靶标。此外，在与精神分裂症的病理生理学有关的前额叶皮质，单个树突棘被两个突触前终末占据；一个轴突终末分泌兴奋性递质(谷氨酸)，另一个分泌多巴胺。人们认为，精神分裂症患者的多巴胺分泌增加，是因为多巴胺受体阻滞剂可以缓解某些症状。我们的工作假设是，异常高的多巴胺分泌抑制了树突的兴奋性，并严重扰乱了单个神经元水平的信息处理(这一过程也被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局部传递到单个树突分支(通过玻璃吸管局部应用神经递质)来模拟谷氨酸和多巴胺能输入的到达。这种方法允许精确控制兴奋性输入到树突树的位置，并具有精确的计时，最重要的是，消除了突触前机制在解释实验结果中的作用。在电压敏感染料的帮助下，将同时分析多巴胺对谷氨酸刺激部位以及邻近既不暴露于谷氨酸也不暴露于多巴胺的树突中树突膜电位的影响。预计拟议的实验将产生更完整的图像，了解多巴胺水平的局部波动如何塑造单个神经元的信息处理，并为精神分裂症的新治疗方法提供动力。

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.