Synaptic integration and calcium signaling are two of the most fundamental functions of neurons. Although models emphasizing the passive spread of potentials dominated early thinking we now know that there are many channel types and signaling molecules distributed over the dendritic arborization that contribute to the amplification of potentials and the activation of regenerative events in different dendritic regions and under different conditions. Exactly how these events are generated and interact is incompletely understood. Several postsynaptic mechanisms appear to particularly important since they are localized in specific dendritic regions and generate large calcium concentration changes. These include NMDA spikes, calcium waves, and localized spine calcium signals. We will use a recently developed a method to simultaneously image sodium and calcium changes in dendrites with high sensitivity and good spatial and temporal resolution. With this technique, combined with classic hippocampal slice electrophysiology and focal glutamate uncaging we will examine the properties of these events. We will explore the heterogeneous generation and propagation of NMDA spikes and calcium release events, determining their spatial boundaries and how they interact to synergistically amplify potentials and generate calcium signals. We will extend these measurements to an examination of some properties of dendritic spines, including the role of voltage dependent sodium channels, spine neck resistance, and the relative contribution of AMPA and NMDA receptor channels on individual spines. Knowledge of these properties is important for both an understanding of basic brain function and for elucidation of how their dysfunction might impact disease processes.
This proposal describes experiments to analyze nonlinear processes in dendrites of hippocampal pyramidal neurons that affect synaptic integration and the generation of calcium signals that affect important signaling mechanisms in dendrites. Of particular interest are NMDA spikes, calcium waves, and spine signals. The experiments will exploit new techniques for simultaneous sodium and calcium imaging. Since these processes are fundamental to neuronal signaling the results will impact our understanding of both normal and pathological brain function.
| Miyazaki, Kenichi; Ross, William N (2017) Sodium Dynamics in Pyramidal Neuron Dendritic Spines: Synaptically Evoked Entry Predominantly through AMPA Receptors and Removal by Diffusion. J Neurosci 37:9964-9976 |
