Theoretical Design, Synthesis, and In Vitro Neurobiological Applications of a Highly Efficient Two-Photon Caged GABA Validated on an Epileptic Case

In this paper, we present an additional, new cage-GABA compound, called 4-amino-1-(4′-dimethylaminoisopropoxy-5′,7′-dinitro-2′,3′-dihydro-indol-1-yl)-1-oxobutane-γ-aminobutyric acid (iDMPO-DNI-GABA), and currently, compound is the only photoreagent, which can be applied for GABA uncaging without experimental compromises. By a systematic theoretical design successful synthesis of several compounds, best reagent exhibits high two-photon efficiency within 700–760 nm range with excellent pharmacological behavior, proved to suitable complex epileptic study. Quantum chemical showed that optimal length cationic side chain enhances absorption by 1 order magnitude due cooperating internal hydrogen bonding extra nitro group on core. This feature increased solubility while suppressing membrane permeability. The was demonstrated in systematic, wide vitro single-cell neurophysiological experiments electrophysiological as well calcium imaging techniques. Scalable inhibitory ion currents were elicited iDMPO-DNI-GABA appropriate spatial–temporal precision, blocking both spontaneous evoked cell activity efficiency. Additionally, demonstrate its applicability real neurobiological study, could smoothly selectively modulate neuronal activities during artificial rhythms first time neural network GCaMP6f transgenic mouse brain slices.