TOWARDS THERAPEUTIC INNOVATION IN TEMPORAL LOBE EPILEPSY: SPATIALLY SELECTIVE AND CLOSED-LOOP ADENOSINERGIC MODULATION OF DENTATE GYRUS EXCITABILITY THROUGH PHOTOPHARMACOLOGY

Reducing hyperexcitability of the dentate gyrus (DG) by focally activating the adenosine A1 receptor (A1R) is a potential therapeutic strategy in mesial temporal lobe epilepsy (MTLE). This study investigated the feasibility of suppressing DG excitability in a spatially selective way and to a predefined level using a closed-loop protocol both ex vivo and in vivo through a photopharmacological approach.
Evoked field postsynaptic potentials (fPSPs) were recorded in the DG and CA1 in acute hippocampal slices from intrahippocampal kainic acid (IHKA)-injected mice incubated with 3µM coumarin-caged N5-cyclopentyladenosine (cCPA), a photocaged A1R agonist. Subregion-selective inhibition of fPSPs was evaluated through spatially restricted illumination of the DG or CA1. The ability to reset DG activation to a predefined level was tested using closed-loop illumination with PS amplitude as the control variable. Finally, after intracerebroventricular injection of 33mM cCPA, closed-loop illumination was applied to maintain DG evoked fPSP amplitude at a target level in a healthy anesthetized mouse.
The fPSP slope decreased selectively upon localized illumination of the DG to 64.8±9.93% in the DG and to 95.2±2.85% in the CA1 (n=6, p<0.001). Using a closed-loop system, the DG PS amplitude was maintained at 50% of baseline in slices (n=5, p<0.001), and in vivo the DG EP amplitude was maintained at 75% of baseline (n=1).
These results indicate that cCPA enables spatially targeted and closed-loop modulation of DG excitability, both ex vivo and in vivo. These findings support the potential of photopharmacology as a targeted therapeutic approach for MTLE.