Optopharmacological control of neurotransmission and excitability in hippocampal slices with a photoactive adenosine A1 receptor agonist

Erine Craey^a, Martijn Risseeuw^b, Serge Van Calenbergh^b, Jeroen Spanoghe^a, Lars Emil Larsen^a, Evelien Carrette^a, Jean Delbeke^a, Kristl Vonck^a, Paul Boon^a, Wytse Wadman^a, Robrecht Raedt^a

^a4BRAIN, Department of Head and Skin, Ghent University, Belgium, Corneel Heymanslaan, 10, Gent, Belgium

^bLaboratory for Medicinal Chemistry, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg, 460, Gent, Belgium

Proceedings of Neural Interfaces and Artificial Senses (NIAS)

Online, Spain, 2021 September 22nd - 23rd

Organizers: Tiago Costa and Georgios Spyropoulos

Oral, Robrecht Raedt, presentation 024
DOI: https://doi.org/10.29363/nanoge.nias.2021.024
Publication date: 13th September 2021

Aim: Adenosine A1 receptors modulate neuronal activity by pre- and postsynaptic routes. The ubiquity of A1 receptors demands focal activation for specific therapeutic intervention. Here we describe how light-triggered release of the coumarin-caged A1 agonist N⁶-cyclopentyladenosine (cCPA) can be used to precisely control CA1 neurotransmission and excitability in acute rat hippocampal slices via a feedback control system.

Methods: Extracellular CA1 field potentials (fEPSPs) were evoked by Schaffer collateral stimulation and recorded with a 60-channel multielectrode array. First the dynamics of the response to CPA were determined using step and pulsed wash-in. Next slices were superfused with 3µM cCPA and 405 nm LED pulses (4mW) of 25/50 ms were used to release CPA. Repeated (10 sec interval) fEPSPs were recorded to monitor CA1 excitability. A light pulse was given each time its amplitude surpassed a preset level; thus constituting an ON/OFF feedback system

Results: CPA modulates fEPSPs with an ED50 of 37 nM and Hill coefficient of 3. Activation time is in the seconds range, while deactivation may take up to 10-20 minutes, reflecting the underlying G-protein signal transduction pathway. CPA effectively reduced excitability, defined as the amount of cell firing induced by synaptic input. The steep concentration dependence and asymmetric dynamics indicate a narrow and complex therapeutic range, but favors frequency modulation by short light pulses that deliver an almost all or none CPA dose. The feedback control kept the fEPSP amplitude stable for over 60 minutes in all slices (n=4) at 50% (or any other level) of its baseline value to within fEPSP variability. Doubling light puls duration reduced flash frequency but increased amplitude variation. Here is still room for refined optimization.

Conclusion: Flash-light uncaging of cCPA was used to precisely and focally control (reduce) CA1 excitability, making it a potential candidate to prevent epileptic seizures.

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