Coordinating Structural Synaptic Plasticity with Intracellular Stores of Calcium

协调结构突触可塑性与细胞内钙储存

• 批准号: 7978412
• 负责人: Jennifer Bourne
• 金额: $ 7.6万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7978412
• 关键词: Acute; Adopted; Adult; Area; Beta-N-Acetylglucosaminidase; Brain; Calcium; Cell Death; Cell Survival; Chemosensitization; Chronic; DNA Sequence Rearrangement; Dendrites; Dendritic Spines; Development; Ensure; Equilibrium; Hippocampus (Brain); Hour; Information Storage; Inositol; Lead; Learning; Length; Long-Term Potentiation; Mediating; Memory; Mental Depression; Mental Retardation; Modeling; Neurodegenerative Disorders; Neurons; Oxidative Stress; Pathway interactions; Pattern; Physiological; Polyribosomes; Process; Protein Biosynthesis; Recovery; Regulation; Resources; Role; Ryanodine; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Signal Transduction; Smooth Endoplasmic Reticulum; Spottings; Stimulus; Structure; Sum; Synapses; Synaptic plasticity; Testing; Time; Training; Transmission Electron Microscopy; Vertebral column; Weight; base; excitotoxicity; insight; nervous system disorder; normal aging; prevent; public health relevance; receptor; therapeutic target

DESCRIPTION (provided by applicant): Structural plasticity of dendritic spines in the hippocampus is essential for learning and the endurance of long- term potentiation (LTP). However, in the mature brain, enhancement of synaptic strength at some synapses must be balanced by a weakening or elimination of other synapses to ensure that the total amount of excitatory input is not in constant flux along a dendritic segment. Recently, we found that 2 hours after the induction of LTP with naturalistic theta burst stimulation (TBS), there was a reduction in the number of small thin spines that was perfectly counterbalanced by an enlargement of PSDs on remaining spines, particularly those containing polyribosomes. The enlargement of PSDs was sufficient to ensure that the total amount of synaptic area supported by the dendrites remained constant following induction of LTP. This suggests that dendrites distribute limited resources such as polyribosomes to spines depending on their level of synaptic activity and raises the question of how the rearrangement of synaptic weight is mediated. We hypothesize that this local coordination is mediated in part by intracellular calcium stored and released from smooth endoplasmic reticulum (SER) that is present throughout the dendritic shaft but only in a subset of dendritic spines. SER is essential for regulation of cytoplasmic calcium during physiological levels of synaptic activation and is a major target of pathological states induced by both acute and chronic neurological disorders. Therefore, a better understanding of SER regulation with normal types of activity such as LTP is crucial to understanding pathological states of calcium regulation. We propose to quantify for the first time the structure and distribution of SER throughout dendrites and spines at 2 hr after the induction of TBS-LTP. We will also determine the role of calcium released from functionally distinct stores in coordinating structural synaptic plasticity along mature CA1 dendrites. PUBLIC HEALTH RELEVANCE: Structural plasticity of dendritic spines and their synapses underlies the storage of information throughout the brain. Many neurological disorders, including mental retardation and neurodegenerative diseases, are correlated with a distortion of spines and dendrites that interferes with the remodeling of synapses. Thus characterizing mechanisms of structural synaptic plasticity will help to identify therapeutic targets for when this process is disrupted. We hypothesize that coordination of structural synaptic plasticity in the hippocampus is mediated in part by intracellular calcium stored and released from smooth endoplasmic reticulum (SER) that is present throughout the dendritic shaft but only in a subset of dendritic spines. Under normal conditions, elevation in cytoplasmic calcium released from intracellular stores is transient and important for triggering multiple pathways involved in plasticity. However, during the progression of neurodegenerative diseases and even normal aging, the ability of neurons to regulate fluxes in calcium can become compromised. Thus SER is important for achieving a balance between enhanced synaptic efficacy observed with the acquisition of information and excitotoxic synaptic activation triggered by pathological states. This proposal will advance our understanding of the relationship between structural synaptic plasticity and regulation of intracellular calcium and perhaps will provide insight into developing treatments that will promote recovery from pathological states without compromising mechanisms of memory.

描述（由申请人提供）：海马中树突棘的结构可塑性对于学习和长时程增强（LTP）的耐受性至关重要。然而，在成熟的大脑中，某些突触的突触强度的增强必须通过其他突触的减弱或消除来平衡，以确保兴奋性输入的总量不会沿着树突节段恒定流动。最近，我们发现，2小时后的诱导LTP与自然theta爆发刺激（TBS），有一个小薄棘的数量减少，这是完全平衡的扩大PSD上剩余的棘，特别是那些含有多聚核糖体。PSD的扩大足以确保树突支持的突触面积的总量在诱导LTP后保持恒定。这表明树突分配有限的资源，如多聚核糖体的棘取决于他们的突触活动水平，并提出了如何介导的突触重量的重排的问题。我们假设，这种局部协调是介导的部分细胞内钙储存和释放的滑面内质网（SER）是目前整个树突轴，但只在一个子集的树突棘。SER对于生理水平的突触激活期间的细胞质钙的调节是必不可少的，并且是由急性和慢性神经障碍诱导的病理状态的主要靶点。因此，更好地了解SER调节与正常类型的活动，如LTP是至关重要的理解钙调节的病理状态。我们建议量化的结构和分布的SER在整个树突和棘在2小时后诱导TBS-LTP的第一次。我们还将确定从功能不同的钙储存释放的作用，在协调结构突触可塑性沿着成熟的CA 1树突。 公共卫生相关性：树突棘及其突触的结构可塑性是整个大脑信息存储的基础。许多神经系统疾病，包括精神发育迟滞和神经退行性疾病，都与干扰突触重塑的棘突和树突的变形有关。因此，表征结构突触可塑性的机制将有助于确定治疗目标时，这一进程被破坏。我们推测，海马结构突触可塑性的协调部分介导的细胞内钙储存和释放的滑面内质网（SER）是目前整个树突轴，但只在一个子集的树突棘。在正常情况下，从细胞内储存释放的细胞质钙的升高是短暂的，并且对于触发涉及可塑性的多个途径是重要的。然而，在神经退行性疾病甚至正常衰老的进展过程中，神经元调节钙流量的能力可能会受到损害。因此，SER是重要的，以实现增强的突触功效与信息的采集和兴奋性毒性突触激活病理状态触发之间的平衡。这一提议将促进我们对结构突触可塑性与细胞内钙调节之间关系的理解，并可能为开发促进病理状态恢复而不损害记忆机制的治疗方法提供见解。