Synaptic Transmission, Plasticity and Integration in the Subthalamic Nucleus

描述(申请人提供)：相关的，低频(&lt；30赫兹)，节律活动的神经元在丘脑底核(STN)的出现是帕金森氏病(PD)症状性表现的关键。来自苍白球外区的GABA能突触输入和来自皮质和丘脑的谷氨酸能突触输入对STN活动的正常和病理模式至关重要。这项研究将检验的主要假设是，帕金森病中多巴胺的丢失导致了STN内异常的突触传递，这(部分)是病理放电模式的基础。这一假说将通过对大脑切片中STN神经元的电生理记录、相关光学和电子显微镜以及双光子成像来验证。多巴胺的影响将通过比较突触传递和整合在1)多巴胺受体激动剂/拮抗剂的存在和不存在和2)在正常和多巴胺耗竭的动物中进行评估。该项目有三个具体目标。具体目的1：测定GABA能和谷氨酸能突触传递的短期可塑性和影响以及多巴胺受体激动剂和拮抗剂对它们的调节作用。具体目标2：确定突触前和/或突触后的活动模式，这是GABA能和谷氨酸能突触传递长期可塑性的基础。具体目的3：比较GABA能和谷氨酸能突触在帕金森病对照动物和实验性帕金森病动物模型中的作用和影响。这个项目所产生的知识将进一步加深我们对STN病理活动潜在因素的理解，并帮助合理开发通过改变STN活动来改善症状和中断PD进展的治疗方法。下层描述：取消丘脑底核(STN)神经细胞的病理活动导致帕金森病(PD)症状的显著改善。该项目将检验病理性STN活动是由帕金森病患者STN神经细胞的异常输入(部分)驱动的假说。通过阐明异常活动的机制，本研究将通过STN活动的正常化来指导合理开发改善症状和阻断PD进展的治疗方法。

DESCRIPTION (provided by applicant): The emergence of correlated, low-frequency (< 30 Hz), rhythmic activity of neurons in the subthalamic nucleus (STN) is critical for the symptomatic expression of Parkinson's disease (PD). GABAergic synaptic inputs from the external globus pallidus and glutamatergic synaptic inputs from the cortex and thalamus are critical for the normal and pathological patterning of STN activity. The principal hypothesis that will be tested by this research is that the loss of dopamine in PD leads to abnormal synaptic transmission within the STN, which (in part) underlies the pathological firing pattern. This hypothesis will be tested using electrophysiological recording of STN neurons in brain slices, correlated light and electron microscopy and 2-photon imaging. The influence of dopamine will be assessed by comparison of synaptic transmission and integration in i) the presence and absence of dopamine receptor agonists/antagonists and 2) in normal and dopamine-depleted animals. There are three specific aims of the project. Specific Aim 1: Measure the short-term plasticity and impact of GABAergic and glutamatergic synaptic transmission and their modulation by dopamine receptor agonists and antagonists. Specific Aim 2: Determine the pre- and/or postsynaptic activity patterns that underlie long-term plasticity of GABAergic and glutamatergic synaptic transmission in the STN. Specific Aim 3: Compare the operation and influence of GABAergic and glutamatergic synapses in the STN in control animals and experimental models of PD. The knowledge generated by this project will further our understanding of the factors underlying pathological activity in the STN and assist the rational development of therapies that ameliorate the symptoms and interrupt the progression of PD by modification of STN activity. Lay Description: Abolition of pathological activity of nerve cells in the subthalamic nucleus (STN) leads to a profound improvement in the symptoms of Parkinson's disease (PD). This project will test the hypothesis that pathological STN activity is driven (in part) by abnormal inputs to STN nerve cells in PD. By elucidating the mechanisms underlying abnormal activity, this research will guide the rational development of therapies that ameliorate the symptoms and interrupt the progression of PD through the normalization of STN activity.