Dopaminergic modulation of dentritic excitability

用于治疗精神分裂症或抑郁症的药物通过调节多巴胺能神经传递发挥作用。这种疗法的确切机制尚不清楚，部分原因是大脑皮层中多巴胺释放的正常生理作用也没有完全了解。在精神分裂症患者死后进行的电子显微镜研究显示，大脑皮层锥体神经元树突的微观结构异常。皮质厚度和树突超微结构的变化， 在死后发现的，可能是由于精神疾病的持续时间很长（一生）和/或很长（慢性）药物治疗。然而，最近的临床研究显示，在精神分裂症患者的灰质体积在疾病的发病初期，从精神病前期到精神病期的过渡期间，有明显的变化。多巴胺能药物的疗效与树突结构和功能受损之间的因果关系是什么？这个问题的答案可能在于大脑前叶中多巴胺能和多巴胺能系统的解剖学并列。 人类大脑，负责认知、计划、控制情绪和决策。在前额叶皮层（一个与精神分裂症的病理生理密切相关的区域），单个树突棘被两个突触前末梢占据;一个轴突末梢分泌兴奋性递质（谷氨酸），另一个分泌调节性递质多巴胺。在发现多巴胺直接突触到皮质锥体神经元的20年后，多巴胺在突触后膜（远端树突）释放的确切功能结果仍然未知。在实验室中，我们通过结合个体的兴奋性突触刺激来模拟多巴胺能和多巴胺能皮层输入的到达。 树突状分支与局部应用多巴胺通过玻璃微量吸管。这种方法允许精确控制树突树中兴奋性输入的位置;精确的定时和持续时间。外源性谷氨酸和多巴胺的局部应用消除了解释实验结果的突触前机制。在电压敏感染料的帮助下，多巴胺对树突膜电位的影响将同时在突触刺激部位以及既不暴露于谷氨酸也不暴露于多巴胺的相邻树突中进行分析。预计拟议的实验将更全面地了解多巴胺水平的局部波动如何影响单个神经元中信号的整合，并为治疗帕金森病的新预防和治疗方法提供动力。 与多巴胺能功能障碍相关的精神障碍。

Medical drugs used in treatment of schizophrenia or depression exert their action through the modulation of dopaminergic neurotransmission. The exact mechanism of such therapy is unknown, partly because the normal physiological role of dopamine release in the cortex is also not fully understood. Electron microscope studies, performed postmortem on the brains of people who suffered from schizophrenia, revealed microscopic structural abnormalities that affect the dendrites of cortical pyramidal neurons. Changes in cortical thickness and dendritic ultrastructure, detected postmortem, could be due to a very long (lifetime) duration of the mental illness and/or a very long (chronic) drug therapy. However, recent clinical studies revealed clear changes in grey matter volume in schizophrenic patients at the very onset of the disease; during the transition from pre-psychotic to psychotic phase. What is the causal relation between the efficacy of dopaminergic drugs, and impairment in dendritic structure and function? The answer to this question may lie in the anatomical juxtaposition of the glutamatergic and dopaminergic systems in the frontal part of human brain, responsible for cognition, planning, control of emotions and decision making. In the prefrontal cortex (an area strongly implicated in pathophysiology of schizophrenia) individual dendritic spines are occupied by two presynaptic terminals; one axon terminal that secretes the excitatory transmitter (glutamate), and the other one that secretes modulatory transmitter dopamine. Twenty years after the discovery of direct dopamine synapse onto a cortical pyramidal neuron, the exact functional consequence of dopamine release at the postsynaptic membrane, in distal dendrites, is still unknown. In the laboratory, we are mimicking the arrival of glutamatergic and dopaminergic cortical inputs by combining excitatory synaptic stimulation of individual dendritic branches with local application of dopamine through a glass micropipette. This approach allows precise control of the location of excitatory input in the dendritic tree; precise timing and duration. Local applications of exogenous glutamate and dopamine eliminate presynaptic mechanisms in the interpretation of experimental results. With the help of voltage-sensitive dyes, the effects of dopamine on dendritic membrane potential will be analyzed simultaneously at the synaptic 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 fluctuations in dopamine level can shape integration of signals in individual neurons, and provide impetus for new preventive and therapeutic approaches in treatment of psychiatric disorders associated with dopaminergic dysfunction.