ACTIONS OF BDNF ON CA2+ SIGNALS IN HIPPOCAMPAL NEURONS

描述：(申请人摘要) 细胞内瞬时抬高的时空分布 棘突和树突内游离钙离子的浓度对 突触发育和成熟。此外，突触的可塑性是 由作用于这些细胞内模式的几种神经调节剂调节 突触前室和突触后室的钙离子浓度。最新发现 提示神经营养因子，包括脑源性神经营养因子 (脑源性神经营养因子)也是突触发育所必需的，对于 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以诱导钙离子升高，特异性的 涉及的机制，钙离子的来源(S)，以及对 突触的发育和可塑性尚不清楚。因此，这一划定 触发这些钙离子升高的突触前和突触后机制中 了解神经营养因子如何调节突触的基础 发育和可塑性。需要检验的具体假设是：BDNF 增强海马CA1区突触活动过程中树突状细胞的钙离子升高 受体酪氨酸激酶(TrkB)激活的锥体神经元 信号通路。树枝状晶的时空分布规律 脑源性神经营养因子引起的钙升高是其最可能的调控机制 突触发育和可塑性。从以下方面获得的基本信息 这些实验将整合脑源性神经营养因子在突触成熟和 可塑性与NMDA受体的要求和区隔 诱导长时程突触所需的树突状钙信号 海马体的变化。 海马体是最敏感的皮质区域之一 神经退行性疾病。由于它在外显学习和记忆中的作用， 严重的认知功能障碍发生在患有 累及海马区的神经退行性疾病 胆碱能系统。神经营养因子与维持性脑脊髓炎有关 成年期的神经元活性，可能是已报道的 神经退行性变患者受损脑功能的神经保护与修复 疾病，如阿尔茨海默氏症。这些神经保护作用 促使人们对它们作为治疗的潜在临床用途进行了重大研究 探员们。了解神经营养因子在突触形成中的作用 维护和可塑性将对 改善认知的治疗策略的发展 在某些神经退行性疾病中发挥作用，例如阿尔茨海默病。

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.