SUMMARY Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

The recent advance in identifying risk genes has provided an unprecedented opportunity for developing animal models for psychiatric disease research with the goal of attaining translational utility to ultimately develop novel treatments. However, at this early stage, successful translation has yet to be achieved. Here, we review recent advances in modeling psychiatric disease, discuss utility and limitations of animal models, and emphasize the importance of shifting from behavioral analysis to identifying neurophysiological defects, which are likely more conserved across species and thus increase translatability. Looking forward, we envision that preclinical research will align with clinical research to build a common framework of comparable neurobiological abnormalities and form subgroups of patients based on similar pathophysiology. Experimental neuroscience can then use animal models to discover mechanisms underlying distinct abnormalities and develop strategies for effective treatments.