Designing a family of photoswitchable NMDA receptor subunits to interrogate receptor functional diversity.

• Applicant: Dr. Viktoria Klippenstein
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277936679

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors (iGluRs) that largely contribute to fast excitatory neurotransmission in the mammalian brain. While normal NMDAR activity is required for fundamental processes such as learning and memory, dysregulation of receptor signaling can be pathological.With their large subunit heterogeneity, tetrameric NMDARs form anatomically and functionally diverse receptor subpopulations. The different subunit compositions of heteromeric complexes endow NMDARs with unique biophysical, pharmacological and signaling properties that crucially depend on the brain region, the developmental stage and synaptic activity. Diverse NMDAR subtypes co-exist not only at the level of different neuronal types, but also within individual neurons, and even at individual synapses, segregating in an input-specific manner. Until now, specific contributions and tasks of the individual NMDAR subtypes to normal and disease central nervous system (CNS) conditions are poorly resolved. The proposed project aims to tackle this question by engineering a family of light-controllable NMDAR subunits. Photoswitchable click amino acids (PSCaa) will be genetically introduced to individual NMDAR subunits, providing highly specific spatiotemporal optical control over the activity of distinct receptor populations. This original opto-chemical approach will provide a novel and powerful tool to identify NMDAR subunit-specific contributions to glutamatergic neurotransmission.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Dr. Pierre Paoletti