Coordinating Structural Synaptic Plasticity with Intracellular Stores of Calcium

描述（申请人提供）：海马体树突棘的结构可塑性对学习和长期增强（LTP）的耐力至关重要。然而，在成熟的大脑中，某些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持续流动。最近，我们发现用自然θ波爆发刺激（TBS）诱导LTP 2小时后，小细棘的数量减少，剩余棘上psd的增加完全抵消了这一减少，特别是那些含有多核糖体的棘。psd的扩大足以确保LTP诱导后树突支持的突触面积总量保持不变。这表明树突将有限的资源，如多核糖体分配给脊椎，这取决于它们的突触活动水平，并提出了突触重量重排是如何介导的问题。我们假设这种局部协调部分是由细胞内钙储存和释放的光滑内质网（SER）介导的，这种钙存在于整个树突轴中，但仅存在于一小部分树突棘中。SER在突触激活的生理水平上对胞质钙的调节至关重要，是急性和慢性神经系统疾病引起的病理状态的主要靶点。因此，更好地了解正常类型的SER调控，如LTP，对于理解钙调控的病理状态至关重要。我们首次提出在TBS-LTP诱导后2小时量化树突和棘中SER的结构和分布。我们还将确定从功能不同的储存中释放的钙在协调成熟CA1树突结构突触可塑性中的作用。

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.