INTRACELLULAR SIGNALS FOR LONG TERM SYNAPTIC DEPRESSION

描述：拟议中的研究检查细胞内信号 小脑浦肯野细胞参与脑性痴呆发生的通路 爬升联合激活的长期抑郁(LTD) 纤维(CFs)和平行纤维(PFS)兴奋性输入。这个 要检验的具体假设是，关联性 LTD的诱导源于两个细胞内的汇合 信号通路、IP3和钙离子。更具体地说，Ltd.是 CFS后诱导的细胞内钙充分升高，以允许PF- 产生IP3，从细胞内释放额外的钙 储存在浦肯野细胞的突触后脊椎内。这个 提案有四个具体目的要调查：1) 代谢型谷氨酸受体(MGluR)在PF信号传导中的作用 钙离子来源于IP3敏感的内储物中诱导的LTD； 3)钙对IP3敏感细胞钙释放的调节 水平；4)如果LTD发生在CFS升高细胞内钙水平之后 足以允许PF产生的IP3从 细胞内存储。调查人员试图实现这些目标 目的利用大鼠小脑片进行一系列实验。 申请人在全细胞记录、离子成像、 共聚焦显微镜和局部闪光光解将应用于 这些实验。

DESCRIPTION: The proposed research examines the intracellular signaling pathways in cerebellum Purkinje cells implicated in the initiation of long-term depression (LTD)by the conjunctive activation of the climbing fibers (CFs) and the parallel fibers (PFs)excitatory inputs. The specific hypothesis that will be tested is that the associative induction of LTD arises from a convergence between two intracellular signaling pathways, IP3 and calcium ions. More specifically, LTD is induced after CFs raise intracellular calcium sufficiently to permit PF- generated IP3 to release additional calcium from the intracellular stores within the postsynaptic spines of the Purkinje cells. The proposal has four specific aims to investigate: 1)the role of metabotropic glutamate receptors (mGluR)in PF signaling; 2)the role of calcium from IP3- sensitive internal stores in the induction of LTD; 3)the regulation of calcium release from IP3 sensitive stores by calcium levels; and 4)if LTD occurs after CFs raise intracellular calcium levels sufficiently to permit PF-generated IP3 to release more calcium from intracellular stores. The investigators seek to achieve these objectives through a series of experiment using rat cerebellar slices. The applicant's expertise with whole-cell recordings, ion imaging, confocal microscopy, and localized flash photolysis will be applied in these experiments.