Chapter 9: From Circuits to Drug Targets: The Promise of Opto- and Chemogenetics for Drug Discovery
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Published:06 Dec 2024
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Special Collection: 2024 eBook CollectionSeries: Drug Discovery Series
D. Kätzel, in Drug Discovery for Schizophrenia
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This chapter describes how genetically targeted expression of remote actuators to control neural activity, either gated by light (optogenetics) or by inert compounds (chemogenetics), can be applied to unravel the circuit mechanisms that underly schizophrenia-related deficits in animal models. These tools are applied within three principal paradigms: (1) the induction approach of causing schizophrenia-related symptoms by targeted circuit manipulation, thereby producing a new class of animal models, (2) the rescue approach of alleviating schizophrenia-related deficits in animal models of the disease to directly establish causality between circuit elements and deficits, and (3) the anatomical and functional characterization of neurons and neural projections thought to be relevant to schizophrenia. In recent years, using all three paradigms, the causal relationships between known endophenotypes seen in schizophrenia patients – such has thalamic hypoactivity, hippocampal hyperactivity, PV-interneuron hypofunction, or dopaminergic aberrations – and schizophrenia-related deficits have been established, thereby confirming novel therapeutic concepts (NTCs) and cellular targets for treatment. The further refinement of circuit models of schizophrenia and the successful translation of cellular targets into druggable molecular targets that can enter clinical development, however, still lie ahead of us.