DISC1-Dependent Antipsychotic Effects of Striatal-Enriched Protein Tyrosine Phosphatase (STEP) Inhibitor, TC-2153, on Mice

Schizophrenia is a severe, chronic mental disorder affecting near 1% of the global population, with about 60% of patients showing resistance to currently available antipsychotic drugs (APDs). The modern dopaminergic (DA) hypothesis of schizophrenia postulates that multiple pathogenic factors contribute to hyperdopaminergia in the striatum. Therefore, effective modulation of striatal DA remains a key strategy in the development of novel APDs. The striatum-enriched protein phosphatase (STEP) is selectively expressed in the dopaminergic neurons of the striatum together with D2 receptors - the main target of existing APDs. In this study, we investigated the APD-like effects of the STEP inhibitor TC-2153 in a genetic mouse model of schizophrenia (Disc1-L100P). We found that TC-2153 [10 mg/kg; i.p.] effectively reduced hyperactivity in Disc1-L100P mutant mice as assessed in the open field test. The STEP inhibitor also ameliorated disrupted latent inhibition (LI) in Disc1-L100P animals, but unexpectedly impaired LI in wild-type (WT) mice. In opposite, TC-2153 had no effect on deficient sensorimotor gating, measured by the pre-pulse inhibition (PPI) paradigm. Additionally, TC-2153 induced antidepressant-like effects in both WT and Disc1-L100P mutant mice, increasing their activity in the Forced Swim Test (FST). These new findings suggest that STEP inhibition produces APD-like effects in a genotype-specific manner while promoting antidepressant-related behavioural phenotypes regardless of genetic background. Overall, our preclinical results support STEP as a promising target for APD development and highlight a potential link between STEP and DISC1 molecular complex in the pathogenesis of schizophrenia – an avenue that warrants further investigation to better understand the molecular mechanisms underlying APD action.