Association Of Decreased Protein Kinase C-β With Immune-inflammatory Mechanism In Major Depressive Disorder

Background: Protein kinase C β(PKCβ)is an essential intracellular second messenger.However,the relation of PKCβ and its isoforms with major depressive disorder mechanism remains unknown.Tumor necrosis factor-α(TNF-α)stimulated downstream cytokine activation relies mostly on PKCβ1 phosphorylation in vascular cells.Here,we investigated the relation of PKCβ and TNF-α levels with brain cortical thickness in drug-naive major depressive disorder(MDD)patients and depressive-like mouse model.Methods: Part 1: A case-control study was conducted to compare differences in PKCβ and TNF-α protein levels and prefrontal cortex cortical thickness between patients with MDD and healthy controls.All the subjects were Han population recruited from Shanghai Mental Health Center.40 MDD outpatients and 40 healthy controls(HC)were recruited for protein(PKCβ1,PKCβ2,and TNF-α)levels measurements and MRI scans.Each patient was untreated with drugs or had a wash-out period for at least three months.Cortical thickness was extracted from MRI images.Part 2: An animal study on depressive-like mouse models,which were established using Corticosterone(CORT)and lipopolysaccharide(LPS),was carried out.Part 3: We measured both PKCβI and PKCβII expression levels in the brain of a depressive-like mouse model to identify the specific brain region in which changed levels of PKCβ expression occurred.Results: In comparison with healthy controls,MDD patients showed significantly lower and higher plasma levels of PKCβI(0.57±0.43 vs.0.82±0.43,F=1.00,P=0.013)and TNF-α(4.64± 0.46 vs.4.36 ±0.34,F=0.122,P=0.004)protein,respectively.In a depressive-like mouse model,a significant decrease of PKCβI(0.43 ± 0.08 vs.1.06 ±0.22 F=5.45,P=0.01)expression was found in the PFC,but not in the hippocampus.There was a negative association between PKCβ1 and TNF-α(r=-0.33,P=0.04)in MDD patients but not in healthy controls.PKCβ1 showed a negative correlation with right frontal pole cortical thickness(r=-0.43,P=0.03).TNF-α showed a significantly positive correlation with the cortical thickness of seven PFC regions,including right caudal middle frontal,right caudal middle frontal,right lateral orbitofrontal,left parsopercularis,left rostral middle frontal,right rostral middle frontal and left supramarginal.Conclusions: These data suggest contributions of decreased expression of PKCβ1and increased expression of TNF-α to prefrontal cortical pathology in MDD patients.The decrease of PKCβ1 in PFC during an early depressive episode protects neurons from neurotoxicity,which could be induced by TNF-α.