Discovering functional interactions among schizophrenia-risk genes by combining behavioral genetics with cell biology

Despite much progress in identifying risk genes for polygenic brain disorders, their core pathogenic mechanisms remain poorly understood. In particular, functions of many proteins encoded by schizophrenia risk genes appear diverse and unrelated, complicating the efforts to establish the causal relationship between genes and behavior. Using various mouse lines, recent studies indicate that alterations of parvalbumin-positive (PV+) GABAergic interneurons can lead to schizophrenia-like behavior. PV+ interneurons display fast spiking and contribute to excitation-inhibition balance and network oscillations via feedback and feedforward inhibition. Here, we first summarize different lines of genetically modified mice that display motor, cognitive, emotional, and social impairments used to model schizophrenia and related mental disorders. We highlight ten genes, encoding either a nuclear, cytosolic, or membrane protein. Next, we discuss their functional relationship in regulating fast spiking and other aspects of PV+ interneurons and in the context of other domains of schizophrenia. Future investigations combining behavioral genetics and cell biology should elucidate functional relationships among risk genes to identify the core pathogenic mechanisms underlying polygenic brain disorders.