Synaptic Transmission, Plasticity and Integration in the Subthalamic Nucleus

描述（由申请人提供）：丘脑底核（STN）神经元出现相关的低频（< 30 Hz）节律性活动对帕金森病（PD）的症状表达至关重要。来自外苍白球的gaba能突触输入和来自皮层和丘脑的谷氨酸能突触输入对于STN活动的正常和病理模式至关重要。本研究将验证的主要假设是，PD中多巴胺的缺失导致STN内突触传递异常，这（部分）是病理性放电模式的基础。这一假设将通过脑切片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进行验证。多巴胺的影响将通过比较1)存在和不存在多巴胺受体激动剂/拮抗剂和2)正常和多巴胺耗尽动物的突触传递和整合来评估。该项目有三个具体目标。具体目标1：测量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。具体目标2：确定突触前和/或突触后活动模式，这些模式是突触神经网络中gaba能和谷氨酸能突触传递长期可塑性的基础。具体目的3：比较对照动物和PD实验模型STN中gaba能突触和谷氨酸能突触的运作及其影响。该项目产生的知识将进一步加深我们对STN病理活动的潜在因素的理解，并有助于合理开发通过改变STN活性来改善症状和中断PD进展的治疗方法。摘要：丘脑下核（STN）神经细胞病理活动的消除导致帕金森病（PD）症状的深刻改善。该项目将验证PD中STN神经细胞的异常输入驱动（部分）病理STN活性的假设。通过阐明异常活动的机制，本研究将指导合理开发通过STN活动正常化来改善症状和中断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.