Proof-of-Concept for α5-GABAAR PAMs in the treatment of psychosis

Recent evidence suggests that a part of the brain called the hippocampus is responsible for the increase in dopamine in a different part of the brain, the striatum, known to cause psychosis. Our hypothesis is that by attenuating activity within the hippocampus, we will then be able to reduce the increase in dopamine associated with psychosis. In order to do this, we plan to target the GABA chemical signalling pathway which inhibits nerve cell excitability. More specifically, we aim to increase the inhibitory actions of the so-called α5-GABAAR protein, which is highly expressed within the hippocampus and is therefore ideally placed to control overall hippocampal activity. In this project, we will identify molecules that selectively enhance the function of GABA at α5-GABAARs and then test representative compounds in an animal model of schizophrenia to see if they do indeed attenuate increased dopamine activity.