The role of presynaptic calcium at ageing synapses

衰老会导致我们记忆能力的下降。有些人相对较好地衰老，而另一些人则受到严重影响。人们最初认为，与年龄相关的认知功能下降是由于大脑中细胞的损失，但现在认为，自然衰老不同于神经退行性疾病，如阿尔茨海默病，在这种疾病中，细胞死亡和结构变化非常明显。在大脑中负责记忆形成和保持的区域，如前额叶皮层和海马体，细胞之间连接的相对微妙的变化可能解释了与年龄相关的记忆形成缺陷。钙在控制细胞内的许多功能，包括细胞间的通讯中起着重要作用。细胞间信号强度的变化被认为提供了一种记忆形成的机制，而这些机制高度依赖于钙。我们已经开发了一种转基因老鼠，它表达了一种能够测量钙的传感器。传感器位于大脑内可兴奋细胞的特殊末端（突触末端），负责释放化学递质，将信息从细胞传递到细胞。在这项应用中，我们希望使用成像技术来测量海马正常活动期间突触终末钙的变化，并将其与显示与年龄相关的记忆下降的老年动物的信号传导进行比较。通过这样做，我们希望了解与年龄相关的大脑功能下降的机制。

Ageing leads to a decline in our ability to remember. Some people age relatively well whereas others are very severely affected. It was originally thought that the age-related decline in cognitive function was due to a loss of cells within the brain but it is now thought that natural ageing is distinct from neurodegenerative conditions, such as Alzheimer's disease, where cell death and structural changes are very apparent. In regions of the brain responsible for memory formation and retention, such as the prefrontal cortex and hippocampus, relatively subtle changes in the connections between cells may account for age-related deficits in memory formation. Calcium plays a fundamental role in controlling many functions within cells including communication between cells. Changes in the strength of signalling between cells are thought to provide a mechanism for memory formation and these are highly dependent up calcium. We have developed a genetically modified mouse that expresses a sensor that is capable of measuring calcium. The sensor is located at the specialised terminals (synaptic terminals) of excitable cells within the brain that are responsible for releasing the chemical transmitters that transfer information from cell to cell. In this application, we wish to use imaging techniques to measure the changes in calcium within synaptic terminals during normal activity within the hippocampus and compare them to signalling in aged animals that display an age-related decrease in memory. In so doing, we hope to understand the mechanisms that are responsible for age-related decreases in brain function.