Feedback Control of Neuronal Excitability and Epileptiform Bursting using a Photocaged Adenosine A1 Agonist

Adenosine is a potent regulator of neurotransmission and neuronal excitability through activation of Gi protein-coupled adenosine A1 receptors (A1Rs). It has gained interest as a potential anticonvulsant due to its endogenous involvement in ending ongoing seizure activity. A recently developed coumarin-caged derivative of the A1R agonist N6-cyclopentyl-adenosine (CPA), cCPA, was used for photo-uncaging of CPA with millisecond flashes of 405 nm light. At population level, CPA reduces Schaffer Collateral stimulated extracellular dendritic field potentials (FPs) in the CA1 region of the hippocampus with an ED50 of 44.1{+/-}2.8 nM and a Hill coefficient of 3. Response onset is CPA dependent and takes less than seconds, while recovery is CPA independent with a time constant of around 20 minutes. A closed-loop feedback system used the amplitude of evoked dendritic FPs to photorelease CPA and was able to control FP amplitude to user defined levels between 10% and 90% of baseline level. In the acute elevated potassium model of epilepsy raising extracellular K+ to 8.5 mM enhances neuronal excitability and induces regularly occurring epileptiform bursts, but FPs evoked with low intensity could still continuously monitor excitability without interfering with bursting. In this model the closed-loop system that controlled CPA release, was able to suppress epileptiform bursting, while maintaining an acceptable level of functional neurotransmission. Including in the control algorithm a second parameter that combined population spike amplitude and number of population spikes, enabled the system to automatically find a level of functional neurotransmission that was just below the threshold for multiple spiking and epileptiform bursting. The combination of photopharmacological adenosinergic modulation with real-time FP monitoring provides a first step towards closed-loop precision treatment for diseases related to neuronal hyperexcitability such as epilepsy.