Theoretical Design, Synthesis, and In Vitro Neurobiological Applications of a Highly Efficient Two-Photon Caged GABA Validated on an Epileptic Case
| Autor: | Zoltán Máté, Zoltán Szadai, Csilla Lukácsné Haveland, Miklós Dékány, Miklós Madarász, Ervin Kovács, Myrtill Majoros, Orsolya Frigyesi, Milán Szőri, Dénes Pálfi, Gergely Katona, Imre G. Csizmadia, Gergely Szalay, Ferenc Erdélyi, Gábor Juhász, Balázs Chiovini, Gábor Szabó, Zoltán Mucsi, Balázs Rózsa |
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| Rok vydání: | 2021 |
| Předmět: |
Membrane permeability
010405 organic chemistry Chemistry General Chemical Engineering General Chemistry Neurophysiology 010402 general chemistry Inhibitory postsynaptic potential 01 natural sciences Article 0104 chemical sciences Electrophysiology Calcium imaging Two-photon excitation microscopy Reagent Side chain Biophysics QD1-999 |
| Zdroj: | ACS Omega ACS Omega, Vol 6, Iss 23, Pp 15029-15045 (2021) |
| ISSN: | 2470-1343 |
| Popis: | 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, this compound is the only photoreagent, which can be applied for GABA uncaging without experimental compromises. By a systematic theoretical design and successful synthesis of several compounds, the best reagent exhibits a high two-photon efficiency within the 700–760 nm range with excellent pharmacological behavior, which proved to be suitable for a complex epileptic study. Quantum chemical design showed that the optimal length of the cationic side chain enhances the two-photon absorption by 1 order of magnitude due to the cooperating internal hydrogen bonding to the extra nitro group on the core. This feature increased solubility while suppressing membrane permeability. The efficiency was demonstrated in a systematic, wide range of in vitro single-cell neurophysiological experiments by electrophysiological as well as calcium imaging techniques. Scalable inhibitory ion currents were elicited by iDMPO-DNI-GABA with appropriate spatial–temporal precision, blocking both spontaneous and evoked cell activity with excellent efficiency. Additionally, to demonstrate its applicability in a real neurobiological study, we could smoothly and selectively modulate neuronal activities during artificial epileptic rhythms first time in a neural network of GCaMP6f transgenic mouse brain slices. |
| Databáze: | OpenAIRE |
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