Research

The dialogue between the synapse and the nucleus controls activity-driven gene transcription. This is vital for virtually all adaptive responses in the nervous system including the build-up of a neuroprotective shield and the formation of memories, but it also regulates unwanted adaptations such as chronic pain or addiction. Calcium signals generated by synaptic activity and the opening of synaptic NMDA receptors and voltage-gated calcium channels serve as initiators of this communication pathway. They also mediate the propagation along the synapse-to-nucleus axis, although additional protein-based transport processes, such as the ERK-MAP kinase cascade, play a role. Nuclear calcium transients represent an important signaling endpoint in synapse-to-nucleus communication and function as master switch for adaptations-associated transcription. Blockade of nuclear calcium signaling in hippocampal neurons eliminates acquired neuroprotection, an activity-driven form of adaptation in which neurons that have been electrically activated are more resistant to harmful, cell death-inducing conditions. Similarly, the consolidation of memories and their extinction, as well as the development of chronic pain in mice is critically dependent on nuclear calcium signaling.

In neurodegenerative conditions this transcription-promoting synapse-to-nucleus communication axis is being antagonized by a cell death promoting signaling pathway activated by extrasynaptic NMDA receptors. Extrasynaptic NMDA receptors cause transcriptional shut-off, mitochondrial dysfunction, and structural disintegration. This ‘pathological triad’ of extrasynaptic NMDA receptor signaling appears to represent a common conversion point in the etiology of several acute and chronic neurodegenerative conditions including stroke, traumatic brain injury, retinal degeneration, Alzheimer’s’ disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). Based on new mechanistic insight into toxic extrasynaptic NMDA receptor signaling, which involves the formation of an extrasynaptic NMDA receptor/TRPM4 death complex, we are currently developing new types of broad-spectrum neuroprotectants.