O-GlcNAcylation and Hippocampal Synaptic Plasticity

描述（由申请方提供）：在基础条件下，大部分葡萄糖通过糖酵解途径代谢，但2- 4%通过己糖胺生物合成途径（HBP）代谢。HBP修饰葡萄糖以产生O-连接的N-乙酰葡糖胺（O-GlcNAc）部分，其可以在高度动态和可逆的反应中添加到蛋白质的丝氨酸/苏氨酸残基。当葡萄糖水平过量时，通过HBP的通量增加，这可导致O-GlcNAc酰化蛋白的病理性增加。两种酶，O-GlcNAc转移酶（OGT）和O-GlcNAc酶分别负责将O-GlcNAc部分添加到蛋白质中的丝氨酸/苏氨酸残基和将O-GlcNAc部分去除。海马神经元中O-GlcNAc转移酶（OGT）和O-GlcNAc酶在前脑的表达最高。 CA 3-CA 1突触功效的长期变化是海马依赖性学习的基础。海马中OGT和O-GlcNAc酶的高表达表明，该脑区域中的正常突触功能受突触蛋白的O-GlcNAc更新调节。然而，关于O-GlcNAc化如何调节突触功能知之甚少。此外，突触蛋白上O-GlcNAc的异常添加可能会干扰突触表达记忆处理所需的长期可塑性的能力，并且可以解释已知在糖尿病动物模型中发生的海马突触功能和学习缺陷，其中O-GlcNAc在病理上升高。迄今为止，没有研究调查在生理或病理条件下O-GlcNAc酰化对记忆形成的影响。 在最近的研究中，我们发现OGT和O-GlcNAcase是紧张性活性的，并且双向调节基础突触传递的强度，这表明通过HBP的自然流量设置回路中的兴奋性水平。此外，我们发现，增加O-GlcNAc酰化限制了突触表达正常LTP的能力，与有限公司没有影响。在这个建议中，我们将调查的细胞和分子机制介导的突触抑郁症引起的增加O-GlcNAc酰化，并确定是否慢性增加O-GlcNAc酰化导致突触功能障碍和学习障碍。因此，O-GlcNAcylation在调节突触传递和可塑性中的生理作用的成功证明可能是学习和记忆领域的下一个重大发现。所获得的结果将启动一个新的研究领域，旨在了解HBP葡萄糖代谢的波动如何直接影响生理和病理条件下的突触功能。

DESCRIPTION (provided by applicant): Under basal conditions, the majority of glucose is metabolized through the glycolytic pathway, but 2-4 % is metabolized via the hexosamine biosynthetic pathway (HBP). The HBP modifies glucose to produce an O-linked N-acetylglucosamine (O-GlcNAc) moiety that can be added to serine/threonine residues of proteins in a highly dynamic and reversible reaction. Flux through the HBP is increased when glucose levels are in excess, which can lead to a pathological increase of O-GlcNAcylated proteins. Two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase are responsible for adding and removing, respectively, the O-GlcNAc moiety to serine/threonine residues in proteins. Hippocampal neurons have the highest expression of O- GlcNAc transferase (OGT) and O-GlcNAcase in forebrain. Long-term changes in the efficacy of CA3-CA1 synapses underlie hippocampal dependent learning. The high expression of OGT and O-GlcNAcase in hippocampus suggests that normal synaptic function in this brain region is modulated by O-GlcNAc turnover of synaptic proteins. However little to nothing is known regarding how O-GlcNAcylation modulates synaptic function. Furthermore, the possibility exists that abnormal addition of O-GlcNAc on synaptic proteins could interfere with the ability of synapses to express long-term plasticity required for memory processing and could explain deficits in hippocampal synaptic function and learning known to occur in animal models of diabetes, where O-GlcNAcylation is pathologically elevated. No study to date has investigated the effects of O-GlcNAcylation on memory formation, either under physiological or pathological conditions. In recent studies, we find that OGT and O-GlcNAcase are tonically active and bidirectionally modulate the strength of basal synaptic transmission, suggesting the natural flux through the HBP sets the level of excitability in the circuit. Furthermore, we find that an increase in O-GlcNAcylation limits the ability of synapses to express normal LTP, with no effect on LTD. In this proposal we will investigate the cellular and molecular mechanisms mediating the synaptic depression induced by increased O-GlcNAcylation and determine whether chronic increases in O-GlcNAcylation causes synaptic dysfunction and learning deficits. Thus, the successful demonstration of a physiological role of O-GlcNAcylation in modulating synaptic transmission and plasticity could be the next major discovery in the field of learning and memory. The results obtained will launch a new area of investigation aimed at understanding how fluctuations in glucose metabolism by the HBP can directly affect synaptic function in physiological and pathological conditions.