Research interests

Changes in the concentration of intracellular calcium as a result of synaptic activity control virtually all adaptive responses in the nervous system. Calcium activates mechanisms that affect synaptic connectivity, regulate learning and memory, promote survival, modulate pain, or cause cell death. Most activity-induced adaptations are initiated by synaptic NMDA receptors and require for their maintenance signal-induced changes in gene expression. For the dialogue between the synapse and nucleus, neurons exploit the spatial and temporal diversity of calcium transients associated with electrical activation. The propagation of calcium signals to the cell nucleus is a major route for synapse-to-nucleus communication. The overall aim of our work is to investigate if and how nuclear calcium and nuclear calcium-regulated gene expression controls activity-dependent neuronal survival and long-term memory. We are developing imaging techniques to visualize nuclear calcium signals both in cell culture and in vivo and use gene chip technology to identify nuclear calcium-regulated genes and test their functional significance. The activities of synaptic NMDA receptors and nuclear calcium signaling to induce transcription and promote survival are antagonized by a calcium signaling pathway that is initiated by calcium flux through NMDA receptors located outside synaptic contacts. Extrasynaptic NMDA receptors couple to a transcription shut-off pathway and cause cell death. We are investigating the relevance of differential signaling by synaptic and extrasynaptic NMDA receptors for neuro-degenerative condition and ageing-related neuronal dysfunction.

 

Methods applied

General molecular biology, gene transcription analyses, RNA interference, cell death and cell survival assays, calcium imaging using small molecule indicators and recombinant probes, confocal microscopy, immunohistochemistry, gene delivery in vitro and in vivo using recombinant adeno-associated viruses, stereotaxic injections, electrophysiology, multi-electrode array recordings, behavioural analysis.