Glutamate is the primary excitatory neurotransmitter in the central nervous system. NMDA receptors (NMDARs) are ionotropic glutamate receptors that detect glutamate in the context of ongoing circuit activity. NMDAR activation requires the binding of glutamate as an agonist and glycine as a co-agonist, together with sufficient membrane depolarization to relieve the voltage-dependent channel block by extracellular Mg2+. In addition, NMDAR function is tightly regulated by a number of endogenous modulators. Upon activation, the NMDAR forms a cation channel highly permeable to Ca2+, a second messenger that coordinates downstream signalling leading to activity-dependent changes in synaptic strength. NMDARs are therefore critical for the development of neural circuits and for their ability to process information.
Pathologies of NMDAR function underlie a range of neurodevelopmental and neuropsychiatric disorders. De-novo mutations in genes encoding NMDA receptor subunits have been identified in individuals with intellectual disability, developmental delay, autism spectrum disorder, epileptic encephalopathy, and schizophrenia. NMDARs also play a role in excitotoxic neurodegeneration.
We use advanced electrophysiology methods, primarily the patch-clamp technique, to study ligand-gated ion channel activity at the level of single channels, whole cells, synapses, and neuronal networks. For the complex understanding of ion channel properties, we combine electrophysiology with quantitative analytical techniques, molecular biology, biochemistry, immunohistochemistry, microfluorometrics, optogenetics, and computational methods (molecular dynamics simulations).
Video: Simulation of conformational changes of the NMDA receptor induced by glutamate binding