Optical control of excitatory transmission in hippocampal slices with photoactive adenosine A1 receptor agonist

Adenosine A1 receptors are capable of modulating neuronal activity by pre- and postsynaptic routes, offering promising possibilities for therapeutic intervention. Unfortunately, their use is limited by the ubiquity of A1 receptors, highlighting the need for focal activation. Optopharmacology allows site-specific agonist release and receptor activation using light-sensitive caged compounds. Here we investigated the UV-triggered activation of the coumarin-caged A1 agonist N6-cyclopentyladenosine (cCPA) in the CA1 region of acute rat hippocampal slices. CA1 field potentials (fEPSPs and population spikes(PS)) were evoked by electrical stimulation of the Schaffer collaterals with variable intensity and recorded using 60-channel multielectrode arrays. Superfusion with 3μM cCPA and UV-pulses (LED: 405nm) at two power intensities (2 and 4mW) for 500 (n=3), 1000 (n=5) and 2000ms (n=5) duration induced transient releases of CPA that modulated synaptic transmission and neuronal excitability as quantified in the local field potentials. They reduced fEPSP slopes for both power intensities and three durations to respectively 81±2%, 55±7% and 40±5% of baseline value. The effects are reversible as demonstrated by the stable and repeated modulation of A1 signalling within the same slice. A similar effect but of larger magnitude was observed for the PS. A computational model allowed us to interpret the observed temporal transients in neuronal excitability and enabled the generation of illumination strategies. These data provide first proof that UV-triggered uncaging of cCPA can be used for controlled transient inhibition of excitatory transmission in slices, making optopharmacology a promising tool for focal modulation of neuronal activity in disease models like epilepsy.