The adenosine A1 receptor (A1R) is a promising therapeutic target in epilepsy by mediating neuronal inhibition. In this study, we investigated whether A1R signaling is still functional in the intrahippocampal kainic acid (IHKA) mouse model for temporal lobe epilepsy (TLE). Moreover, we evaluated the feasibility of spatial selective inhibition of specific hippocampal subregions through photopharmacology. Electrically evoked field postsynaptic potentials (fPSPs) were recorded in the CA1 and DG of acute hippocampal slices. The effect of adding 40 nM of the A1R agonist N6cyclopentyladenosine (CPA) on population spike (PS) amplitude to fPSP slope, an index of excitability, was evaluated in epileptic IHKA versus healthy mice. Subregion selective inhibition of fPSPs was evaluated through application of 405nm light pulses (10 pulses of 100ms at 0.1Hz) spatially restricted to CA1 or DG of healthy slices incubated with 3µM coumarin-caged CPA (cCPA). Administration of CPA similarly decreased hippocampal excitability in epileptic versus healthy mice for CA1 (n=8) and DG (n=12, p<0.01 for CPA effect, p>0.05 for CPA-by-group interaction, linear mixed model). In a slice incubated with cCPA, excitability decreased selectively in the illuminated hippocampal subregion (n=1, Figure). To conclude, the decrease in excitability is comparable in hippocampal slices of IHKA versus healthy mice upon exposure to CPA, indicating preserved A1R signaling in IHKA mice. The use of cCPA allows modulation of hippocampal subregions through localized illumination. These results indicate that photopharmacology has the potential to become a targeted therapy for TLE. This research is funded by the Ghent University Special Research fund.