F86. Molecular mechanism of the TNIK gene affecting the action of antipsychotic drugs through the glutamate pathway

Background Schizophrenia (SCZ) is a complex psychiatric disorder primarily treated with antipsychotic drugs (APDs), yet the response to these treatments shows significant individual variability. Between 40 % and 80 % of patients exhibit minimal or no response to these medications, and some experience severe adverse effects. Genetic factors play a crucial role in these individual differences. Previous research revealed that three SNPs within the intronic regions of the TNIK gene, rs2088885, rs7627954, and rs6444970, are significantly associated with the efficacy of APDs. However, the specific mechanisms of how TNIK affects the efficacy of antipsychotic drugs remain unknown. TNIK is a susceptibility gene for schizophrenia and is closely related to glutamate metabolism, which may play a crucial role in the response to antipsychotic drugs. Hence, this study investigates the impact of the TNIK on changes in the glutamate pathway induced by antipsychotic drugs. Results The regulatory functions results revealed that the genomic regions of rs2088885 and rs7627954 exhibit promoter activity, while the genomic region of rs7627954 also exhibited enhancer activity. The wild-type region of rs6444970 did not show any apparent regulatory effect, however, mutation in this region demonstrated significant enhancer activity. These findings suggest that the three polymorphic sites, rs2088885, rs7627954, and rs6444970, may have a substantial impact on the expression of the TNIK gene. Subsequently, a TNIK knockdown SH-SY5Y cell model was established using siRNA interference techniques. RT-qPCR analysis post-treatment with antipsychotic drugs risperidone and clozapine revealed significant increases in the expression of key enzymes in the glutamate pathway, GLS, GLUL, and GLUD. Knockdown of TNIK further elevated the expression of these enzymes, suggesting that TNIK may play a crucial role in maintaining glutamate homeostasis. Morpholino technology was used to knockdown the zebrafish homolog of TNIK (tnika). Phenotypic observations revealed developmental anomalies such as axial curvature, cardiac edema, increased mortality, and reductions in head area and eye diameter, suggesting that tnika affects early head development and neurodevelopment in zebrafish. Post-treatment with risperidone in zebrafish, RT-qPCR results indicated that tnika knockdown further increased the expression of glutamate pathway genes (glula, glulb, glsa, glsb, and glud1), consistent with cellular findings, suggesting that tnika might play a role in maintaining glutamate metabolic homeostasis. Its deficiency leads to glutamate metabolism disorder, impacting the efficacy of APDs. Discussion In conclusion, this study aims to elucidate the function of TNIK in the action of antipsychotic drugs, particularly its effect on the glutamate pathway. The findings suggest that TNIK may influence APDs efficacy through its impact on glutamate metabolism.