Optical control of NMDA receptors with a diffusible photoswitch

Abstract

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory, and are implicated in various neuronal disorders. We synthesized a diffusible photochromic glutamate analogue, azobenzene-triazole-glutamate (ATG), which is specific for NMDARs and functions as a photoswitchable agonist. ATG is inactive in its dark-adapted trans-isoform, but can be converted into its active cis-isoform using one-photon (near UV) or two-photon (740 nm) excitation. Irradiation with violet light photo-inactivates ATG within milliseconds, allowing agonist removal on the timescale of NMDAR deactivation. ATG is compatible with Ca2+ imaging and can be used to optically mimic synaptic coincidence detection protocols. Thus, ATG can be used like traditional caged glutamate compounds, but with the added advantages of NMDAR specificity, low antagonism of GABAR-mediated currents, and precise temporal control of agonist delivery.

Recent Advances of Light-Mediated Theranostics

“…So far, numerous photosensitive structures such as azobenzene 52, 53, spiropyran 56, 57 and diarylethene 58, 59 etc (Figure 3A), have been well utilized for the light-mediated bioimaging and therapy. For instance, Zhao et al fabricated a smart self-assembled vesicle via the host-guest interaction between azobenzene derivative and β-cyclodextrin (β-CD) (Figure 3B) 54.…”

Precise modulation of neuronal activity with synthetic photoswitchable ligands

“…Recently both PCL and PTL approaches were developed for NMDARs. The PCL agonist ATG is unreactive in its relaxed trans -isomer, but when irradiated with UV light, the cis -isomer is an agonist for multiple NMDAR subunits (GluN2A,B,C,D)[5]. Experiments in slices of mouse cortex show that ATG can be used to induce currents and action potentials, even in place of synaptic stimulation for signal coincidence detection.…”

“…Neurons[48,49] and astrocytes[48] expressing LiGluR and labeled with a PTL give a photocurrent with 2P excitation, and even neuron spiking. Further, 2P activation of LimGluRs[49,50], as well as the PCL ATG, which targets NMDARs[5] were reported.…”

Optical control of neuronal activity using a light-operated GIRK channel opener (LOGO)

“…15 This approach, termed photopharmacology, is able to confer exquisite spatiotemporal control onto biological systems using the unrivalled precision of light and has previously been used to optically control ion channels, 16 GPCRs, 17 enzymes 18 and antibiotics. 19 …”