Plasticity of Striatal Glutamatergic Synapses in Parkinson's Disease

帕金森病纹状体谷氨酸突触的可塑性

基本信息

批准号：
8416254
负责人：
Yoland Smith
金额：
$ 36.41万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416254
关键词：
Affect Animal Model Animals Antiparkinson Agents Basal Ganglia Brain Cells Cerebral cortex Chronic Complement Complex Corpus striatum structure Data Dendritic Spines Development Dopamine Dopamine Agonists Electric Stimulation Electron Microscope Electrons Electrophysiology (science)Fiber Functional disorder Funding Glutamate Receptor Glutamates Goals In Vitro Lesion Location MPTP Poisoning Measures Mediating Methods Microscopic Midbrain structure Modeling Monkeys Morphology Motor Neuronal Plasticity Neurons Output Parkinson Disease Parkinsonian Disorders Physiological Physiology Plastics Process Publishing Regulation Relative (related person)Resolution Rodent Slice Source Synapses System Techniques Testing Thalamic structure Trees Vertebral column awake base density immunoreactivity in vivo neurochemistry neurotransmission nonhuman primate public health relevance receptor reconstruction research study response transmission process vesicular glutamate transporter 1

项目摘要

DESCRIPTION (provided by applicant): The striatum is the main entrance of extrinsic information to the basal ganglia circuitry. It is largely made up of medium sized GABAergic neurons characterized by densely spiny dendritic trees, the so- called "medium spiny neurons (MSNs)". The cerebral cortex and the thalamus are the two main sources of excitatory glutamatergic afferents to MSNs. Midbrain dopaminergic inputs tightly regulate striatal glutamatergic neurotransmission. Lesion of the nigrostriatal dopaminergic system in animal models of Parkinson's disease (PD) results in a dramatic loss of dendritic spines accompanied with altered transmission and plasticity of corticostriatal synapses. During the past funding period, we characterized in detail the synaptic connectivity of striatal glutamatergic afferents in nonhuman primates using the vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2) as specific markers of corticostriatal and thalamostriatal systems, respectively. Our data also provided further evidence for a major loss of dendritic spines and a relative increase in vGluT1 immunoreactivity in the striatum of MPTP-treated parkinsonian monkeys, thereby extending previous evidence for alterations in corticostriatal transmission in Parkinsonism. During the next funding period, we propose to extend these recent findings and further investigate plastic changes in spine morphology and AMPA glutamate receptor subunits localization that could possibly underlie functional alterations in corticostriatal and thalamostriatal glutamatergic transmission in Parkinsonism. These anatomical studies will be complemented with an in vivo assessment of changes in the physiological responses of striatal MSNs to activation of the corticostriatal system in awake MPTP-treated parkinsonian monkeys. Our proposal aims at achieving the following three goals: (1) To characterize the morphology and ultrastructural features of dendritic spines that receive cortical and thalamic inputs in the striatum of normal and parkinsonian monkeys, (2) To characterize and compare the subcellular and subsynaptic localization of the AMPA GluR1 subunit in spines contacted by cortical or thalamic inputs in normal and MPTP-treated parkinsonian monkeys and (3) To compare the electrophysiological effects of cortical stimulation upon striatal projection neurons activation between normal and parkinsonian monkeys, and determine if dopaminergic antiparkinsonian therapy mediates its beneficial effect through regulation of corticostriatal glutamatergic transmission . Together, these studies will provide highly significant information that will help further understand the physiology, pathophysiology and structural plasticity of the two main glutamatergic systems that regulate striatofugal neurons activity under normal and parkinsonian conditions.

描述（由申请人提供）：纹状体是向基底神经节电路的外部信息的主要入口。它主要由中等大小的GABA能神经元组成，其特征在于密集的树突状树，即所谓的“中刺神经元（MSN）”。大脑皮层和丘脑是MSN兴奋性谷氨酸能传入的两个主要来源。中脑多巴胺能输入严格调节纹状体谷氨酸能神经传递。帕金森氏病动物模型（PD）中斑纹纹状体多巴胺能系统的病变导致树突状棘的急剧丧失，并伴随着皮层突触的变速器和可塑性的改变。在过去的资金期间，我们使用囊泡谷氨酸转运蛋白1和2（vglut1和vglut2）分别详细介绍了非人类灵长类动物中纹状体谷氨酸能传入的突触连通性（VGLUT1和VGLUT2）作为皮质术和丘脑tri骨系统的特定标记。我们的数据还提供了进一步的证据，证明了树突状刺的重大损失以及MPTP处理的帕金森尼猴子纹状体中VGLUT1免疫反应性的相对增加，从而扩展了parkinsonism中皮质纹状体传播改变的证据。在下一个资金期间，我们建议扩展这些最新发现，并进一步研究脊柱形态和AMPA谷氨酸受体亚基的塑性变化，这些变化可能是帕克森氏症中皮质纹状体和丘脑纹状腺乳面菌疗法传播的功能改变的基础。这些解剖学研究将在体内评估纹状体MSN对醒着MPTP治疗的Parkinsonian猴子中皮质纹状体系统的生理反应变化的变化。 Our proposal aims at achieving the following three goals: (1) To characterize the morphology and ultrastructural features of dendritic spines that receive cortical and thalamic inputs in the striatum of normal and parkinsonian monkeys, (2) To characterize and compare the subcellular and subsynaptic localization of the AMPA GluR1 subunit in spines contacted by cortical or thalamic inputs in normal和MPTP处理的帕金森尼猴子和（3），以比较皮质刺激对正常和帕金森尼猴子之间纹状体投影神经元激活的电生理影响，并确定多巴胺能抗蛋白酶治疗是否通过调节皮质型胶质性胶原性胶原性型的介导其益处。总之，这些研究将提供高度重要的信息，这些信息将有助于进一步了解两个主要的谷氨酸能系统的生理，病理生理和结构可塑性，这些系统在正常和帕金森氏症情况下调节纹状体神经元活性。