Chemogenetic approach to model hypofrontality

Clinical evidence suggests that the prefrontal cortex (PFC) is hypofunctional in disorders including schizophrenia, drug addiction, and attention-deficit/hyperactivity disorder (ADHD). In schizophrenia, hypofrontality has been further suggested to cause both the negative and cognitive symptoms, and overactivity of dopamine neurons that project to subcortical areas. The latter may contribute to the development of positive symptoms of the disorder. Nevertheless, what causes hypofrontality and how it alters dopamine transmission in subcortical structures remain unclear due, in part, to the difficulty in modeling hypofrontality using previous techniques (e.g. PFC lesioning, focal cooling, repeated treatment with psychotomimetic drugs). We propose that the use of designer receptors exclusively activated by designer drugs (DREADDs) chemogenetic technique will allow precise interrogations of PFC functions. Combined with electrophysiological recordings, we can investigate the effects of PFC hypofunction on activity of dopamine neurons. Importantly, from a drug target discovery perspective, the use of DREADDs will enable us to examine whether chemogenetically enhancing PFC activity will reverse the behavioral abnormalities associated with PFC hypofunction and dopamine neuron overactivity, and also explore druggable targets for the treatment of schizophrenia and other disorders associated with abnormalities via modulation of the G-protein coupled receptor signaling pathway. In conclusion, the use of the DREADDs technique has several advantages over other previously employed strategies to simulate PFC hypofunction not only in terms of disease modeling but also from the viewpoint of drug target discovery.