ACTIONS OF BDNF ON CA2+ SIGNALS IN HIPPOCAMPAL NEURONS

描述：（申请人摘要） 细胞内蛋白质的瞬时升高的时空模式 棘和树突内游离钙离子的浓度对于 突触发育和成熟。此外，突触可塑性是 受几种神经调节剂的调节，这些神经调节剂作用于细胞内 突触前和突触后室中的Ca 2+浓度。最近的调查结果 表明神经营养因子，包括脑源性神经营养因子 （脑源性神经营养因子），也是必要的突触发育，以及为 诱导和维持突触强度的长期变化。虽然 神经营养因子已被证明可诱导Ca2+升高， 所涉及的机制，Ca2+离子的来源，以及 突触发育和可塑性尚不清楚。因此， 触发这些Ca2+升高的突触前和突触后机制是 神经营养因子如何调节突触 发展和可塑性。待检验的具体假设是：BDNF 在海马CA1区突触活动期间增强树突状Ca 2+升高 通过受体酪氨酸激酶（TrkB）的激活， 信号通路树突状细胞的时空调控 BDNF引起的Ca2+升高是其调节脑缺血的最可能机制。 突触发育和可塑性。基本信息来自 这些实验将整合BDNF对突触成熟的作用， 可塑性与NMDA受体的要求和区室化 树突状细胞的Ca 2+信号诱导长时程突触 海马体的变化 海马体是最易受影响的皮质区域之一， 神经退行性疾病由于它在外显学习和记忆中的作用， 认知能力的严重损害发生在患有 神经退行性疾病涉及海马区神经支配 胆碱能系统神经营养因子与维持 成年期的神经元活力，可能是报告的基础 神经保护和恢复神经退行性疾病中受损的脑功能 疾病，如阿尔茨海默病。这些神经保护作用 促使人们对它们作为治疗药物的潜在临床用途进行了重大研究 剂.了解神经营养素在突触形成中的作用， 维持和可塑性将作出根本性的贡献， 开发治疗策略以改善认知功能 在某些神经退行性疾病中起作用，如阿尔茨海默病。

DESCRIPTION: (Applicant's Abstract) The spatial and temporal patterns of transient elevations of the intracellular concentration of free calcium ions within spines and dendrites are crucial for synapse development and maturation. Furthermore, synaptic plasticity is regulated by several neuromodulators acting on those patterns of intracellular Ca2+ concentration in both pre and postsynaptic compartments. Recent findings indicate that neurotrophins, including brain-derived neurotrophic factor (BDNF), are also necessary for synapse development, as well as for the induction and maintenance of long-term changes in synaptic strength. Although neurotrophins have been shown to induce Ca2+ elevations, the specific mechanisms involved, the source(s) of Ca2+ ions, and the consequences for synaptic development and plasticity are not known. Therefore, the delineation of the pre and postsynaptic mechanisms triggering those Ca2+ elevations is fundamental to the understanding of how neurotrophins modulate synaptic development and plasticity. The specific hypothesis to be tested is: BDNF enhances dendritic Ca2+ elevations during synaptic activity in hippocampal CA1 pyramidal neurons by the activation of the receptor tyrosine kinase (TrkB) signaling pathway. The regulation of the spatio-temporal patterns of dendritic Ca2+ elevations by BDNF is the most likely mechanism for its modulation of synaptic development and plasticity. The fundamental information gained from these experiments will integrate the role of BDNF on synaptic maturation and plasticity with the requirement of NMDA receptors and compartmentalized dendritic Ca2+ signals necessary for the induction of long-term synaptic changes in the hippocampus. The hippocampus is one of the most susceptible cortical regions to neurodegenerative diseases. Due to its role in explicit learning and memory, severe impairments in cognitive performance occur in patients suffering neurodegenerative diseases involving hippocampal areas innervated by cholinergic systems. Neurotrophins have been implicated in the maintenance of neuronal viability in adulthood, possibly underlying the reported neuroprotection and restoration of impaired brain function in neurodegenerative disorders, such as Alzheimer's disease. These neuroprotective effects have prompted significant research on their potential clinical use as therapeutic agents. Understanding the role of neurotrophins in synapse formation, maintenance and plasticity will make fundamental contributions to the development of therapeutic strategies for the improvement of cognitive functions in certain neurodegenerative diseases, such as Alzheimer's disease.