Utility and validity of DISC1 mouse models in biological psychiatry

Abstract

We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10-15 years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of the major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit-level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future.

Keywords: DISC1; mouse models; psychiatry.

Figure 1. Disrupted in System Connectivity: how DISC1 dysfunction leads to behavioral manifestation?

This diagram summarizes how DISC1 elicits its functions at the molecular and cellular levels, leading to modulation of a series of neurotransmitter systems, as well as neural circuitry, which ultimately determine a range of behavioral domains, such as emotion and cognition. Deregulated DISC1 function primarily leads to impairment of neuronal development, signaling, and synaptic activities, which, coupled with various environmental insults, further affect neurotransmitter systems and neural circuitry, leading to manifestation of behavioral abnormalities. Dimensional characterization of a range of research domains affected by DISC1 dysfunction will help understand the pathophysiological mechanisms underlying human psychiatric conditions. Note that, in essence, DISC1 should not be synonymous with the gene disrupted in schizophrenia; it should rather be recognized as a gene disrupted in system connectivity.