Optogenetic and Chemogenetic Tools for Drug Discovery in Schizophrenia
Advances in clinical genetics, brain imaging, histopathology and neurophysiology point strongly to schizophrenia as fundamentally a disorder of neural circuitry. Schizophrenia research, including drug discovery, would therefore benefit greatly from recently developed tools for precise control of neural circuits in experimental animals. Two sets of tools to manipulate genetically defined populations of neurons and pathways are especially likely to be invaluable for further progress: using light (optogenetics), and using otherwise pharmacologically inert drugs (chemogenetics). This chapter reviews the wide range of optogenetic and chemogenetic tools currently available, and outlines some essential steps for their implementation in the laboratory. Finally, important studies are described, which exemplify the range of applications of such tools, including their promises and pitfalls, on the way to dissecting the circuit basis of psychiatric disease and drug action. Generally, such tools can be applied in one of three scenarios: (1) the induction of schizophrenia-related behaviour by targeted circuit manipulation, thereby producing a new class of animal models of the disease, (2) the rescue of schizophrenia-related deficits in animal models, which is necessary to establish causality between circuit alterations and symptoms, and (3) the anatomical and functional characterization of neurons and neural projections relevant to schizophrenia, including opto- and chemogenetic pharmacology.