Optical control of glutamate receptors of the NMDA-kind in mammalian neurons, with the use of photoswitchable ligands

N-Methyl-d-aspartate receptors (NMDAR) are members of the glutamate binding ligand-gated receptors. They are primarily found at excitatory synapses, essential for some of the most prominent forms of synaptic plasticity pertaining to learning and memory (Nabavi et al., 2014; Bliss and Lomo, 1973) and their dysfunction underlies diverse diseases (Newcomer et al., 2000; Burnashev and Szepetowski, 2015). By combining genetic manipulations of NMDAR subunits and synthetic chemical photoswitches, we have recently developed a family of light-gated, or photoswitchable, NMDA receptors to gate plasticity in vitro and in vivo. This approach—synthetic optogenetics (Berlin and Isacoff, 2017)—enables to confer remote, rapid, and reversible optical modulation of NMDA receptors of a particular subunit composition. This chapter describes the use of azobenzene-based tethered photoswitches and engineered NMDAR subunits to engender the NMDA-receptor light-sensitive; in cultured hippocampal neurons.