SYNAPTIC PHARMACOLOGY OF SINGLE SUBTHALAMIC NEURONS

描述：(改编自申请者的摘要)电生理学研究将在大鼠脑片上进行，以检查丘脑下丘脑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-羟基多巴胺(6-OHDA)治疗的大鼠和左旋多巴治疗的动物进行比较，这将使人们能够深入了解帕金森氏症。具体目标1致力于表征电压依赖电流和多巴胺对体外培养的丘脑下丘脑神经元膜特性的影响。这些研究将解决这样一种假设，即对丘脑底核神经元的长期刺激会降低它们的活动，这是因为电压门控钙电流的持续失活或谷氨酸受体的脱敏。这一假说将具体说明刺激这一区域的“脑深部刺激”如何产生临床效果。具体目标2将研究多巴胺、ACh和其他递质对丘脑下部和黑质网状核神经元突触电流的影响。选择多巴胺和乙酰胆碱是合乎逻辑的，因为这些递质可能具有正常的作用。有一个特定的假设需要解决，即慢性多巴胺耗竭和左旋多巴治疗，类似于帕金森症，将改变受体药理学。实验将如何解决这一假说并不像在特定目标1中那样清楚。特定目标3将确定导致丘脑下丘脑神经元爆发放电的离子机制。多巴胺能操纵的调节也将被研究。了解爆发式放电的重要性在于，这种类型的活动比单一放电更有可能影响靶神经元。了解丘脑底核的输出显然与理解运动障碍和帕金森症有关。具体目标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中的GABA和M受体都有慢性影响。因此，推测这种治疗方法会影响丘脑下部和黑质网状核神经元的突触电位。因此，用6-羟基多巴胺损毁或左旋多巴治疗的大鼠，将在体外检查丘脑底核和黑质网状核的突触变化。

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.