Mapping age-related dysregulation of in vivo synaptic plasticity to molecular synaptic diversity

将体内突触可塑性的年龄相关失调映射到分子突触多样性

• 批准号: BB/X010171/1
• 负责人: Kjara Pilch
• 金额: $ 51.8万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX010171%2F1
• 关键词: Mapping; age; related; dysregulation; vivo

Synapses are highly specialised structures consisting of a presynaptic (sender) and postsynaptic (receiver) site to connect neuronal cells and enable communication. In the cortex, most connections are mediated via small membranous protrusions called dendritic spines, which make up the postsynaptic site. Synapses exhibit a high degree of diversity in their function and protein composition. Moreover, protein levels can be dynamically altered, for example during synaptic plasticity. During synaptic plasticity, adjustments in synaptic strength underlie the encoding of new information during learning and memory. To avoid excessive or insufficient firing rates, homeostatic mechanisms are in place. A dysregulation of plastic adaptations is thought to underly pathological levels of brain activity and has also been observed in early stages of dementia in the ageing brain.A fundamental challenge is to understand how different protein compositions of spines relate to healthy synapse function and plastic adaptations. Recently, the Barnes laboratory has found discrete clusters of plastic and non-plastic spines in the visual cortex of mice. They also revealed, that in the aged brain, some forms of synaptic plasticity at dendritic spines are changed. However, how synaptic function relates to molecular diversity remains unclear. In this project I hypothesize that discrete populations of molecularly defined synapses map to specific classes of synaptic function and plasticity in vivo. I will establish how a dysregulation of these synaptic clusters leads to synaptic dysfunction in the ageing brain.I will first demonstrate different functional clusters of dendritic spines in vivo. For this, I will perform calcium imaging experiments of dendritic spines in awake mice during normal behaviour and after the induction of plasticity to determine functional spine clusters. To map functional clusters to their protein composition, I will induce plasticity in brain slices and assess protein levels with multiplexed proteomics. Finally, to assess changes in spine plasticity in the ageing brain, calcium imaging experiments, proteomics and follow-up super resolution microscopy will reveal changes in different spine populations in older mice.This research will be crucial for our understanding of synaptic function and spine dynamics in the ageing brain. Particularly the possibility to correlate functional clusters from in vivo experiments to their molecular composition at the single synapse level makes these findings so valuable. This research is highly relevant with important implications for further translational research. Identifying the molecular basis of changes that drive synaptic dysfunction in the ageing brain may open new avenues for clinical interventions in cognitive decline and dementia.

突触是高度特化的结构，由突触前（发送者）和突触后（接收者）组成，用于连接神经元细胞并使其能够通信。在皮层中，大多数连接是通过称为树突棘的小膜状突起介导的，树突棘构成突触后部位。突触在功能和蛋白质组成上表现出高度的多样性。此外，蛋白质水平可以动态改变，例如在突触可塑性期间。在突触可塑性过程中，突触强度的调整是学习和记忆过程中新信息编码的基础。为了避免过度或不足的发射速率，体内平衡机制到位。可塑性适应的失调被认为是大脑活动病理水平的基础，在老年大脑痴呆的早期阶段也被观察到。一个基本的挑战是理解不同的蛋白质组成如何与健康的突触功能和塑性适应相关。最近，巴恩斯实验室在老鼠的视觉皮层中发现了离散的塑料和非塑料棘簇。他们还发现，在衰老的大脑中，树突棘的突触可塑性的某些形式发生了变化。然而，突触功能与分子多样性之间的关系尚不清楚。在这个项目中，我假设分子定义的突触的离散种群映射到体内突触功能和可塑性的特定类别。我将确定这些突触簇的失调如何导致老化大脑中的突触功能障碍。我将首先在体内展示树突棘的不同功能簇。为此，我将对清醒小鼠在正常行为和诱导可塑性后的树突棘进行钙成像实验，以确定功能性脊柱簇。为了将功能簇映射到它们的蛋白质组成，我将诱导大脑切片的可塑性，并使用多重蛋白质组学评估蛋白质水平。最后，为了评估老化大脑中脊柱可塑性的变化，钙成像实验、蛋白质组学和后续超分辨率显微镜将揭示老年小鼠不同脊柱种群的变化。这项研究将是至关重要的，我们的理解突触功能和脊柱动力学在老化的大脑。特别是将体内实验中的功能簇与单个突触水平上的分子组成联系起来的可能性使这些发现非常有价值。本研究对进一步的翻译研究具有重要意义。识别驱动老化大脑突触功能障碍变化的分子基础可能为认知能力下降和痴呆的临床干预开辟新的途径。