NMDA receptors are fundamental for both the physiology and the pathology of the mammalian central nervous system. They control plasticity-related events and adaptive processes in the nervous system, which includes long-term potentiation (LTP), memory formation and the build-up of a neuroprotective shield. However, NMDA receptors can also bring about destruction and cell death. The discovery that the location of the NMDA receptor matters resolved the ‘NMDA receptor paradox’ and provided a unifying concept. NMDA receptors localized to the synapse and activated by synaptic inputs promote neuronal survival, gene expression and plasticity. In contrast, NMDA receptors that are located outside synaptic contacts – the so-called extrasynaptic NMDA receptors – couple to transcriptional shut-off and death signaling pathways. Increased extrasynaptic NMDA receptor signaling is now considered a key factor in disease progression of several human neurodegenerative disorders, including Amyotrophic Lateral Sclerosis, Huntington’s disease, Alzheimer’s disease, and stroke. Extrasynaptic NMDA receptors have become an important target for the development of therapeutic interventions. 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.

More information:

• https://www.izn.uni-heidelberg.de/en/research/izn-investigators/prof-dr-hilmar-bading