Use of novel ligands to dissect the control of neural circuits by the neuromodulator adenosine

Neural circuits in the brain which control specific behaviours consist of groups of neurons linked by classical fast excitatory and inhibitory synapses. However an often neglected component of such circuits are diffusive neuromodulators, which can change the way circuits function Such a neuromodulator is the purine adenosine, which is released by neurons and glia during neural activity and then via activation of A1 receptors provides a tuneable negative feedback control mechanism. Activation of A1 receptors has two major effects: inhibition of synaptic transmission and hyperpolarisation of the membrane potential of neurons (by opening K+ channels) reducing their likelihood of firing action potentials. Until now these two effects of A1 receptor activation could not be pharmacologically or genetically separated. However we have developed new A1 receptor ligands which show receptor signalling bias and these allow us dissect apart the multiple effects of A1 receptor activation. The aim of this project is to use these novel ligands as tools to fully understand the roles of the different components of A1 receptor activation in circuit function. In particular investigating hippocampal, neocortical and thalamocortical circuits which are activated by different forms of activity. This project aims to understand basic mechanisms underlying normal brain function which may become compromised in disease states.