Saturation of Synaptic Plasticity at Individual Dendritic Spines

摘要 生物体的学习能力对于它们生存和适应新环境至关重要。学习依赖于 对大脑改变神经元之间的连接以改变电路功能或突触可塑性的能力。 突触可塑性的调节功能障碍，或大脑对刺激做出反应的能力， 与神经系统疾病如阿尔茨海默氏病、自闭症谱系障碍和药物成瘾有关。 许多关于学习相关突触可塑性的研究都集中在树突棘上， 膜突起，是皮层中兴奋性传递的突触后位点。值得注意的是， 在一个叫做间隔学习的过程中，当休息被纳入学习过程时，人类的学习能力会得到改善。 值得注意的是，间隔训练增加了脆性X染色体、安格尔曼综合征和唐氏综合征啮齿动物模型的学习能力， 有学习障碍的孩子一种观点认为，断裂的需要是由于塑性的暂时饱和， 参与这种学习的突触事实上，已经表明，增强作用的饱和导致 动物模型中的学习障碍。在初始刺激导致回路增强后，第二刺激 除非刺激之间的间隔增加，否则不能产生增强作用。然而，机制 导致塑性饱和的因素仍然没有得到很好的定义。该提案的目标是确定蜂窝 以及这种饱和发生的分子机制。我目前的数据显示， 加强发生在单个突触水平，饱和通过突触后机制发生。 我的数据还表明，在个别棘突触强化饱和可以克服， 刺激水平增加，并且当刺激60分钟后刺激脊柱时，饱和度也随时间释放 它们的初始刺激能够表现出进一步的突触强化。最后，我的数据显示CaMKII 在经历饱和的棘中活动减少。使用双光子（2p）成像，2p谷氨酸 uncaging，钙成像和条件性单细胞敲除动物，我建议严格调查 分子和细胞机制驱动个体棘的可塑性饱和。的结果予以 实验将进一步加深我们对突触可塑性及其局限性的认识，并可能阐明新的药物 治疗神经系统疾病和学习障碍的目标。在完成我的论文后，我 我打算攻读博士后职位，研究线粒体信号传导和功能障碍在 神经退行性疾病拟议的实验和培训计划将为以下方面提供坚实的基础： 我的过渡到博士后培训，并将支持我在我的学术研究职位的长期目标。

Abstract The ability of organisms to learn is crucial for them to survive and adapt to new environments. Learning relies on the brain’s capacity to change the connections between neurons to alter circuit functions, or synaptic plasticity. Dysfunction in the regulation of synaptic plasticity, or ability of the brain to change in response to stimuli, has been implicated in neurological disorders like Alzheimer’s disease, autism spectrum disorder and drug addiction. Much of the research on the synaptic plasticity associated with learning has focused on dendritic spines, membranous protrusions that are the postsynaptic sites of excitatory transmission in the cortex. Notably, learning in humans is improved when breaks are incorporated into learning sessions, in a process called spaced learning. Notably, spaced training increases learning in rodent models of Fragile X, Angelman’s and Down syndromes, which are learning impaired. One idea is that the need for breaks is due to a temporary saturation of plasticity at the synapses involved in this learning. Indeed, it has been shown that saturation of potentiation leads to impairment of learning in animal models. After an initial stimulation leads to circuit potentiation, a second stimulus is unable to produce potentiation unless the intervals between stimuli were increased. However, the mechanisms that lead to saturation of plasticity remain poorly defined. The goal of this proposal is to determine the cellular and molecular mechanisms by which this saturation occurs. My current data show that saturation of synaptic strengthening occurs at individual synapse level and that the saturation occurs via postsynaptic mechanisms. My data also demonstrate that saturation of synaptic strengthening at individual spines can be overcome by increased levels of stimulation and that saturation is also release over time as spines stimulated 60 minutes after their initial stimulation are able to exhibit further synaptic strengthening. Finally, my data show that CaMKII activity is reduced in spines which are experiencing saturation. Using 2-photon (2p) imaging, 2p glutamate uncaging, calcium imaging and conditional single cell knock out animals, I propose to rigorously investigate the molecular and cellular mechanisms that drive saturation of plasticity at individual spines. The results of these experiments will further our knowledge of synaptic plasticity and its limitations and could elucidate novel drug targets for the treatment of neurological disorders and learning disabilities. After completing my dissertation, I intend to pursue a postdoctoral position studying the role of mitochondrial signaling and dysfunction in neurodegenerative diseases. The proposed experiments and training plan will provide a strong foundation for my transition to postdoctoral training and will support me in my long-term goal of an academic research position.