SYNAPTIC PHARMACOLOGY OF SINGLE SUBTHALAMIC NEURONS

描述：（改编自申请人摘要）电生理研究将在大鼠脑切片上进行，以检查丘脑下神经元的兴奋性和抑制性输入的特征。正常大鼠的记录将与6-羟多巴胺（6-OHDA）治疗的大鼠和左旋多巴治疗的动物的记录进行比较，这将有助于深入了解帕金森病。特异性目的1致力于电压依赖性电流的表征和多巴胺对丘脑下神经元膜特性的影响。这些研究将解决长时间刺激丘脑下神经元降低其活性的假设，因为电压门控钙电流持续失活或谷氨酸受体脱敏。这一假设将具体说明如何刺激这一区域“深部脑刺激”可能产生临床效果。具体目标2将研究多巴胺、乙酰胆碱和其他递质对丘脑下和黑质网状神经元突触电流的影响。多巴胺和乙酰胆碱的选择是合乎逻辑的，因为这些递质可能正常发挥作用。有一个特定的假设需要解决，即慢性多巴胺消耗和左旋多巴治疗，类似于帕金森氏症，会改变受体药理学。实验验证这一假设的方式并不像具体目标1那样明确。具体目标3将确定负责在丘脑下神经元爆发放电的离子机制。多巴胺能操纵的调节也将被检查。理解突发放电的重要性在于，这种类型的活动比单次放电更有可能影响目标神经元。了解丘脑下核的输出将明显与理解运动障碍和帕金森病相关。特异性目的4是基于先前的研究表明多巴胺耗竭/左旋多巴治疗对基底神经节的GABA和毒蕈碱受体都有慢性影响。因此，我们假设这种治疗会同时影响丘脑下和黑质网状神经元的突触电位。因此，用6-羟多巴胺损伤或左旋多巴治疗的大鼠将在体外检查丘脑下核和黑质网状质的突触变化。

DESCRIPTION: (adapted from applicant's abstract) Electrophysiological studies will be conducted in rat brain slices to examine the characteristics of excitatory and inhibitory inputs to subthalamic neurons. Recordings in normal rats will be compared to those of rats treated with 6-hydroxydopamine (6-OHDA) and levodopa-treated animals, which will allow insight into Parkinson's disease. Specific aim 1 is devoted to characterization of voltage-dependent currents and effects of dopamine on membrane properties of subthalamic neurons in vitro. These studies will address the hypothesis that prolonged stimulation of subthalamic neurons reduces their activity because of persistent inactivation of voltage-gated calcium currents or desensitization of glutamate receptors. This hypothesis will specifically address how stimulation of this region "deep brain stimulation "may yield a clinical effect. Specific aim 2 will examine the effects of dopamine, ACh, and other transmitters on synaptic currents in both subthalamic and substantia nigra - reticulata neurons. The choice of dopamine and acetylcholine is logical given that these transmitters are likely to have effects normally. There is a specific hypothesis to be addressed, that is, chronic dopamine depletion and levodopa treatment, akin to Parkinonism, would alter receptor pharmacology. The manner that the experiment will address this hypothesis is not as clear as in specific aim 1. Specific aim 3 will identify ionic mechanisms that are responsible for burst firing in subthalamic neurons. Modulation by dopaminergic manipulations will be examined also. The importance of understanding burst firing is that this type of activity is more likely than single discharge to influence target neurons. Understanding the output of the subthalamic nucleus will clearly have relevance for understanding movement disorders and Parkinsonism. Specific aim 4 is based on previous studies showing that dopamine depletion/levodopa treatment both have chronic effects on GABA and muscarinic receptors in the basal ganglia. Thus it is hypothesized that this treatment will influence the synaptic potentials in both the subthalamic and substantia nigra- reticulata neurons. Therefore, rats which are lesioned with 6-hydroxydopamine or treated with levodopa will be examined in vitro for synaptic changes in the subthalamic nucleus and substantia nigra-reticulata.