Integration of synaptic excitation and inhibition in the deep cerebellar nuclei

 描述(申请人提供)：小脑核(CBN)神经元是小脑的主要输出，参与运动协调，包括来自小脑皮质浦肯野(PKJ)细胞的抑制和来自苔藓纤维和下橄榄的兴奋。CBN细胞的功能障碍导致运动疾病，如共济失调和肌张力障碍。最近的工作表明，在短暂的IPSP期间，PKJ简单尖峰的同步性抑制了CBN细胞的自发放电，但允许IPSP后的短潜伏期尖峰；这种周期性的抑制/去抑制使CBN细胞的放电与同步的PKJ细胞的自发放电相锁定。在这项提案中，现在 实验旨在研究苔藓纤维驱动的突触兴奋如何调制CBN细胞对抑制的反应。在34-37℃的GABAA受体拮抗剂中，从P17-P23小脑切片中的大投影CBN细胞进行全细胞记录，以阻断内源性抑制。来自PKJ细胞的抑制性突触电导将被动态钳制施加，而苔藓纤维的突触兴奋将被电刺激激活。将应用不同的兴奋和抑制模式和数量，并检查CBN细胞在突触整合过程中的激发反应。这些数据将提供对小脑信息编码机制的洞察。

 DESCRIPTION (provided by applicant): Neurons of the cerebellar nuclei (CbN), which are the main output of the cerebellum and involved in motor coordination, integrate inhibition from Purkinje (Pkj) cells of the cerebellar cortex and excitation from mossy fibers and inferior olive. Dysfunction of CbN cells contributes to motor diseases like ataxia and dystonia. Recent work showed that synchrony of Pkj simple spikes inhibits spontaneous firing by CbN cells during brief IPSPs, but permits short-latency spiking after IPSPs; this periodic inhibition/disinhibition lets CbN cells phase- lock their firing to that of synchronized Pkj cells. In this proposal, the present experiments are designed to investigate how mossy-fiber-driven synaptic excitation modulates CbN cell responses to inhibition. Whole-cell recordings will be made from large projection CbN cells in P17-P23 mouse cerebellar slices at 34-37°C in GABAA receptor antagonists to block endogenous inhibition. Inhibitory synaptic conductances from Pkj cells will be applied by dynamic clamp and synaptic excitation from mossy fibers will be activated by electrical stimulation. Different patterns and amounts of excitation and inhibition will be applied and CbN cell firing responses during synaptic integration will be examined. These data will provide insights into mechanisms of information encoding in the cerebellum.