Phasic dopamine and symptom domains of mental illness

Project Summary Activity patterns in the brain establish how information is perceived and processed. Disruptions of these patterns are likely a major contributor to the pathophysiological basis of mental disorders. Neurons in the ventral midbrain system play an essential role in learning and motivation and mutations within several genes known to regulate action potential firing patterns have been identified in psychiatric disorders, yet virtually nothing is known of the impact of these mutations on neuronal physiology, circuit function, and social behavior. We have demonstrated that inactivation of different ion channels associated with the pathophysiological basis of mental disorders can have differential effects on neuronal physiology and phenotypic outcomes. Neurons of the ventral midbrain express a suite of channels that regulate the action potential waveform and activity patterns. Based on these diverse functions, we propose that elucidating the physiological and phenotypic outcomes associate with a gain or loss of function of these proteins will provide important insight into how their disruption yields a mosaic of behavioral phenotypes. To this end, we have developed a viral vector-based systems for rapid mutagenesis and expression of pathogenic mutations in midbrain cells and demonstrated that altered function of different channels yields both overlapping and non-overlapping behavioral phenotypes in mice. The experiments proposed here will further elucidate common and uncommon phenotypic outcomes and the impact of specific mutations on the operation of distinct dopamine subsystems.