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

Background: Protein kinase C ?(PKC?)is an essential intracellular second messenger.However,the relation of PKC? and its isoforms with major depressive disorder mechanism remains unknown.Tumor necrosis factor-?(TNF-?)stimulated downstream cytokine activation relies mostly on PKC?1 phosphorylation in vascular cells.Here,we investigated the relation of PKC? and TNF-? 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 PKC? and TNF-? 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(PKC?1,PKC?2,and TNF-?)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 PKC?I and PKC?II expression levels in the brain of a depressive-like mouse model to identify the specific brain region in which changed levels of PKC? expression occurred.Results: In comparison with healthy controls,MDD patients showed significantly lower and higher plasma levels of PKC?I(0.57±0.43 vs.0.82±0.43,F=1.00,P=0.013)and TNF-?(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 PKC?I(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 PKC?1 and TNF-?(r=-0.33,P=0.04)in MDD patients but not in healthy controls.PKC?1 showed a negative correlation with right frontal pole cortical thickness(r=-0.43,P=0.03).TNF-? 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 PKC?1and increased expression of TNF-? to prefrontal cortical pathology in MDD patients.The decrease of PKC?1 in PFC during an early depressive episode protects neurons from neurotoxicity,which could be induced by TNF-?.