A specific GPR56/ADGRG1 splicing isoform is associated with antidepressant response in major depressive disorder

Major Depressive Episode (MDE) is one of the most common psychiatric disorders. Often difficult to treat, this disease is one of the leading causes of suicide. A recent study showed an association between GPR56/ADGRG1 mRNA, MDE and response to antidepressant treatment in blood and in brain. Among GPR56 splicing variant, the S4 isoform has recently been associated with microglial synaptic pruning, while microglia are already known as a central player in MDE. Therefore, we hypothesized that S4 is the specific isoform associated to MDE and antidepressant response. To test our hypothesis, an in silico analysis was first performed to identify the different proteins and transcript isoforms of GPR56. This analysis allowed to design PCR and qPCR primers. GPR56 total, S4 and S3 were assessed by RT-qPCR in leukocytes from a cohort of 46 MDE patients including non-responders (NR, n=31) and responders-remitters (R, n=17) to antidepressant treatment. We replicated the result of one of our previous studies, which described an increase in total GPR56 mRNA in Rs. Additionally, we observed that this variation differs among mRNA splicing variants, with S4 exhibiting a similar pattern of variation while S3 shows no significant change. The differences observed withstood statistical correction for covariates of interest such as smoking, gender and suicidal ideation, demonstrating the robustness of the model. These findings confirm our hypothesis that certain mRNA splicing variants of GPR56 may play a more significant role in depression. This study highlighted a link between the GPR56-S4 and response to antidepressant treatment.