Calcium Signals in Neurons During Early Development: Experiments and Theory

钙在神经元信号传导中起着重要的作用，它既是细胞膜上的电荷载体，又是生物化学的第二信使。在这个项目中，我们的目标是在出生后早期大脑发育过程中，它在神经元回路形成中的作用，其特征是树突、棘和突触的产生和消除。神经元的可塑性和电路的形成依赖于细胞质钙的升高，这是树突和丝状的生长以及脊柱形成所必需的。我们最近证明，细胞内储存的钙通过ryanodine受体释放能够产生参与树突棘可塑性的信号纳米结构域（Johenning et al., PlosBiology, 2015）。我们建议采用跨学科的实验和理论方法来研究钙信号与脊柱形成之间的功能相互作用。钙的动力学是一种在空间和时间上高度可变的现象。胞质内钙水平通过质膜内流和细胞内储存通过受体通道协调释放而改变。一旦钙被释放，它就会扩散到细胞质中，并增加邻近细胞内钙通道打开的可能性。这提供了一种自我放大机制，这对钙波的产生至关重要。利用先进的实验技术，我们将描述钙源的分布，重点关注细胞内树突的储存和钙信号的影响因素。理论研究将在实验结果的基础上提出并研究树突和棘中钙波的定量模型。理论方法，特别适用于钙浓度的多尺度性质，允许对钙在微纳米域的局部分布进行详细的研究，这是荧光显微镜无法获得的。我们的跨学科方法将进一步确定钙信号的空间模式，以棘的分布和树突的分支模式。我们旨在了解钙信号如何控制新生儿神经回路的发育。

Calcium is a key player in neuronal signaling, since it can serve both as electrical charge carrier at the membrane and biochemical second messenger. In this project we aim at its role in neuronal circuit formation during early postnatal brain development, which is characterized by the generation and elimination of dendrites, spines, and synapses. Neuronal plasticity and circuit formation have been shown to depend on cytoplasmic calcium elevations, which are necessary for dendritic and filopodial outgrowth as well as spine formation. We recently demonstrated that calcium release from intracellular stores via ryanodine receptors is able to generate signaling nanodomains involved in plasticity of dendritic spines (Johenning et al., PlosBiology, 2015).We propose to investigate the functional interaction between calcium signals and spine formation in an interdisciplinary experimental and theoretical approach. The dynamics of calcium is a phenomenon highly variable in space and time. Cytosolic calcium levels are modified by influx from the plasma membrane and the coordinated release from intracellular stores through receptor channels. Once calcium is released it diffuses into the cytosol and increases the open probability of neighboring intracellular calcium channels. This provides a self-amplifying mechanism, which is crucial for the generation of calcium waves.Using advanced experimental techniques we will characterize the distribution of calcium sources with a focus on intracellular stores in dendrites and the contributing factors for calcium signals. Theoretical research will then be based on the experimental results to propose and study a quantitative model of calcium waves in dendrites and spines. The theoretical methods, specifically adapted to the multi-scale nature of calcium concentration, allow a detailed investigation of the local distribution of calcium in micro- and nanodomains, which is not accessible by fluorescence microscopy. Our interdisciplinary approach will further identify the spatial patterning of calcium signals to the distribution of spines and branching pattern of dendrites. We aim at understanding how calcium signals govern the development of neonatal circuits.