408. DIFFERENTIAL GENE EXPRESSION INVOLVING THE EPIDERMAL GROWTH FACTOR (EGF) AND IMMUNE SYSTEM PATHWAYS IN DORSOLATERAL PREFRONTAL (BA46) AND ORBITOFRONTAL (BA11) CORTICAL REGIONS IN MOOD DISORDERS

Abstract Background Major depression, bipolar disorder are linked by multiple common genetic and environmental risk factors but the trajectories of these factors to result in the different illnesses is still unknown. Considerable evidence implicates immune dysregulation in mood disorder pathology with involvement of stress response genes suggesting reactions to environmental insults. In addition, neurodevelopmentally linked growth factor systems such as the epidermal growth factor (EGF) system is of interest given its involvement in neural processes such as synaptic plasticity disrupted in these disorders. Therefore, we sought to determine if immune and EGF system genes interacted in mood disorders to mediate the impact of environmental risk factors in the pathology of these disorders. Aims & Objectives To examine if key EGF and immune signalling pathways are differentially expressed in brain in mood disorder patients and if there could be any interactions between them. Method The expression of candidate genes from EGF and immune systems and related signalling pathways were examined in post-mortem dorsolateral prefrontal (DLPFC) (n=114 genes) and orbitofrontal cortical (OFC) (n=105 genes) tissues, from mood disorder (n=30), schizophrenia (n=18), and healthy (n=20) subjects, using RT-qPCR. Protein levels of 8 immune molecules were measured by western immunoassay in these brain regions. Data were analysed by ANOVA or corresponding non-parametric tests. General linear modeling (GLM) was used to test for interactions between EGF and immune pathway molecules. Results In DLPFC, there were 64 differentially expressed genes (DEG) between patient and healthy control groups. Of these, 19 were significantly altered in mood disorder predominantly in mTOR, TNF, toll-like receptor (TLR) and complement signalling pathways with minimal changes noted in MAPK-ERK, PI3K-AKT, cytokine signalling and JAK-STAT pathways. ERBB4 was uniquely changed in mood disorder and was the only upregulated gene in a patient cohort. Forty-three of the DEG (67%) were significantly altered between the patient groups, with all of them exhibiting the lowest expression in schizophrenia. In OFC, only three genes were differentially expressed across the groups and IKBKG was significantly downregulated in mood disorder against controls. There were no protein changes in mood disorder patients either in BA46 or BA11. Significant interactions between EGF system molecules BRAF and PIK3CA, and immune signalling through IFNA1 in mood disorder were noted. Discussion & Conclusions We found that although there were common changes in the mTOR, TLR and the TNF signalling pathways between the schizophrenia and mood disorder cohorts, expression profiles between them were highly different. Particularly, the unique upregulation of ERBB4 receptor in mood disorder may carry pathological significance and indicate that the ErbB-PI3K-AKT-mTOR signalling axis may be differently regulated from schizophrenia in DLPFC. These findings overall may signify some important pathological differences in EGF and immune system signalling between these disorders. Further, those immune pathways altered in mood disorder indicate attenuation in innate immune response in these disorders suggesting possible association to early environmental insults. There may be regional differences between BA46 and BA11 in EGF and immune system dysfunction in mood disorders.