Coordinating Structural Synaptic Plasticity with Intracellular Stores of Calcium

描述(申请人提供)：海马树突棘的结构可塑性对学习和长时程增强(LTP)的耐力是必不可少的。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削弱或消除其他突触来平衡，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，在自然的theta Burst刺激(TBS)诱导LTP 2小时后，细小的脊椎数量减少，这被剩余脊椎上PSD的增大所完全抵消，特别是那些含有多聚核糖体的脊椎。PSD的扩大足以确保在LTP诱导后，树突支持的突触总面积保持不变。这表明，树突根据其突触活动水平将有限的资源(如多聚核糖体)分配给棘突，并提出了突触重量重排是如何调节的问题。我们推测，这种局部协调部分是通过细胞内钙离子的储存和释放来实现的，这些钙离子存在于整个树突干中，但只存在于树突棘的一个子集中。在突触激活的生理水平上，丝氨酸是调节细胞内钙离子的关键，也是急、慢性神经系统疾病引起的病理状态的主要靶点。因此，更好地了解正常活动类型的SER调节，如LTP，对于理解钙调节的病理状态至关重要。我们建议首次在TBS-LTP诱导后2小时量化SER在树突和棘中的结构和分布。我们还将确定从功能不同的储存库释放的钙在沿着成熟的CA1树突协调结构突触可塑性方面的作用。 与公共健康相关：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。许多神经疾病，包括智力低下和神经退行性疾病，都与棘突和树突的扭曲有关，这种扭曲干扰了突触的重塑。因此，表征结构突触可塑性的机制将有助于确定这一过程何时被破坏的治疗靶点。我们推测，海马区结构突触可塑性的协调部分是通过细胞内钙的储存和释放来实现的，该细胞内钙存在于整个树突干中，但只存在于树突棘的一部分。在正常情况下，细胞内钙释放的升高是短暂的，对于触发参与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发展过程中，神经元调节钙离子流动的能力可能会受到损害。因此，SER对于在信息获取过程中观察到的突触效率增强和病理状态触发的兴奋性毒性突触激活之间实现平衡是重要的。这一建议将促进我们对结构突触可塑性与细胞内钙调节之间的关系的理解，并可能为开发在不损害记忆机制的情况下促进病理状态恢复的治疗方法提供启示。

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.