GABA channels and dopamine in striatum

描述（由申请人提供）：纹状体控制习得运动行为的执行以及抑制不需要的运动。纹状体中的主要神经元类型是中棘神经元（MSN），它接受来自皮质和丘脑的会聚谷氨酸神经支配以及来自黑质的多巴胺神经支配。此外，一小部分gaba能中间神经元控制大量msn的兴奋性，以维持信息流出的适当平衡，从而顺利控制运动输出。这种控制是通过相性和强直性GABAa受体激活来实现的。本项目旨在比较纹状体和纹状体神经通路中GABA受体介导的电流和受体亚型。我们将利用在D1或D2多巴胺受体表达细胞中选择性表达绿色或红色荧光蛋白的小鼠品系的皮质纹状体切片来鉴定这些细胞中GABAa受体的独特特性。皮质纹状体切片的单细胞电生理学将用于验证纹状体GABAa受体的一部分具有独特的性质，并且在纹状体投射神经元的两种主要亚型之间分布不均匀的假设。基于初步数据显示纹状体MSN表达一种由GABAa通道亚型介导的强直传导，第一个具体目标将努力了解GABAa受体的α和β亚基在MSN中产生这种强直激活中的作用。这将通过亚基选择性药物、缺乏特定亚基的小鼠和与纹状体单胞神经网络相关的重组GABA通道来完成。第二个目标将测试蛋白质激酶磷酸化调节强直活性GABA通道的功能特性的假设。最后一个目的是研究MSN亚型中特异性和独特的多巴胺受体的存在是否在GABA受体亚型的特性设定和表达调节中起作用，GABA受体亚型可以作为纹状体功能障碍相关疾病的药物治疗靶点。

DESCRIPTION (provided by applicant): The striatum controls the execution of learned motor behaviors as well as the suppression of unwanted movements. The main neuronal type in the striatum, the medium spiny neuron (MSN), receives converging glutamatergic innervation from the cortex and thalamus and dopaminergic innervation from the substantia nigra. In addition a small population of GABAergic interneurons controls the excitability of a vast population of MSNs to maintain the proper balance of information outflow for smooth control of motor output. This control is exerted via both phasic and tonic GABAa receptor activation. This project aims to compare GABA receptor-mediated currents and the receptor subtypes amongst MSNs originating the striatopallidal and the striatonigral pathways. We will utilize corticostriatal slices made from strains of mice which selectively express green or red fluorescent protein in D1 or D2 dopamine receptor expressing cells to identify unique properties of GABAa receptors in these cells. Single cell electrophysiology in corticostriatal slices will be used to test the hypothesis that that a portion of striatal GABAa receptors have unique properties and are unequally distributed between the two major subtypes of striatal projection neurons. Based on preliminary data showing that striatopallidal MSN express a tonic conductance mediated by a subtype of GABAa channel, the first specific aim will strive to understand the role of alpha and beta subunits of GABAa receptors in producing this tonic activation in MSNs. This will be done with subunit selective drugs, mice lacking specific subunits and recombinant GABA channels relevant to striatal MSNs. The second aims will test the hypothesis that protein kinase phosphorylation regulates the functional properties of tonically active GABA channels. The last aim will investigate if the presence of the specific and distinct dopamine receptors in MSN subtypes plays a role in setting the properties and regulating the expression of GABA receptor subtypes that can be target for pharmacological therapy of disorders associated with striatal dysfunction. PUBLIC HEALTH RELEVANCE: Striatopallidal and striatonigral medium spiny neurons are the major output neurons from the mammalian striatum, control movements and become imbalanced in movement disorders. Previous reports have suggested that dopamine depletion induces changes in GABA receptors which exacerbate this imbalance of striatal output. Additionally, the systemic administration of the GABAA receptor agonist muscimol, increased locomotor activity in dopamine receptor D2 knockout mice, a model of Parkinson's disease while reducing locomotion in wild type mice. Using transgenic mice with the two major striatal output pathways labeled, we will have a unique opportunity to answer a fundamental question: What role tonic and phasic GABA conductance plays in striatal disorders? As GABAa receptor have a quite established pharmacology, the proposed study has great potential to identify novel therapeutic targets for treating disorders associated with striatal dysfunction including Parkinson's disease, Huntington's disease, tardive dyskinesia, Tourette's syndrome and drug addiction. In addition, as the pharmacology of two major classes of DA receptors has such critical role in mental illness, the results we will derive, although clearly related to basic neuroscience, will have notable applications to both neurological disorders and to mental health.