The Expression Of PRKCB1 And INPP4A In Patients With Major Depressive Disorder And The Role Of Their Downstream Molecule BDNF In Differential Diagnosis Between Unipolar And Bipolar Depression

[Background and Objective] Intracellular second messenger and signal transduction cascade are considered to be playing an important role in the neurobiological mechanisms of major depressive disorder,which may be the novel targets for the treatment of major depressive disorder(MDD).Abnormalities in immunoinflammatory responses and structural neuroimaging have been well documented in MDD in previous studies.Based on the previous genome-wide analysis and their roles in neuroinflammation and neural plasticity,we analyzed the protein expression of INPP4 A and PRKCB1 in plasma of MDD patients and further evaluated the value of their downstream molecule BDNF in differential diagnosis of MDD and bipolar depression(BD-D).This previous study may be conducive to the early recognition,the pathological mechanism and comorbidity mechanism of MDD.[Methods] Part 1 the protein expression of PRKCB1 gene and INPP4 A gene in MDD patients: A total of 40 patients with MDD and 40 normal controls were enrolled.INPP4 A protein expression and PKC isoforms(?I and ?II)were assessed using western blot analysis,and TNF-? was measured using enzyme-linked immunosorbent assay(ELISA)kits.The volume of grey matters and regions was obtained from the Siemens 3.0 magnetic resonance(MRI)scanning.We compared levels of PKC? and INPP4 A protein,levels of TNF-? and volume of brain gray matter between MDD group and healthy controls.We also did the correlation analysis between protein levels and TNF levels as well as protein levels and volume of brain gray matter.Part 2 the role of BDNF in differential diagnosis between unipolar and bipolar depression: A total of 105 participants were recruited in the present study including 44 healthy controls,37 MDD patients and 24 BD-D patients.We applied ELISA kits to measure plasma mBDNF levels and proBDNF levels of all participants.[Results]Part1: MDD patients showed significantly lower plasma PKC?? and significantly higher TNF-? levels(P=0.013 and 0.005,respectively),when compared with healthy controls except PKC??(P=0.704).There was a negative association between PKC?? and TNF-?(r=-0.373,P=0.018)in MDD patients.No significant association was detected between PKC??,PKC?? and TNF-? in healthy controls(P=0.989 and 0.855,respectively)as well as PKC?? and TNF-?(r=0.008,P=0.960)in MDD patients.There may be difference of INPP4 A protein levels between the two groups(P = 0.066).In MDD group,PKC?? has a negative correlation with the total brain gray matter volume,the hippocampal volume,the caudate nucleus volume,and there may be a negative correlation with the cerebellum volume and cerebral cortex volume.INPP4 A may have a positively correlation with the cerebral cortex volume.Part2: BD-D group showed significantly decreased plasma mBDNF levels than MDD group(P=0.001)and healthy controls(P=0.002).At baseline,significantly higher ratio of mBDNF to proBDNF(M/P)was showed in MDD group compared with BD-D group as well as in healthy controls(P=0.000 and P=0.000,respectively).The M/P ratio was the optimal model for discriminating BD-D(area under the ROC curve=0.858,95%CI: 0.753-0.963).Furthermore,after antidepressants treatment,the M/P ratio was restored to normal levels in MDD group.[Conclusions]The results showed that MDD patients has different levels of PKC?? but PKC??,which may favor the closer relationship of PKC?? and MDD.The results suggested that PKC?? may participate in the inflammatory response and lead to the change of brain structure in MDD patients.The abnormal INPP4 A protein expression in MDD patients was not proved in this study,but it suggests a tendency to be abnormal and to be associated with the volume of cerebral cortex.This study found both plasma mBDNF levels and M/P ratio were lower in BD-D compared with MDD.In conclusion,our study support PKC?? may play an important role in the pathogenesis of depression and further support M/P ratio as a potential differential diagnostic biomarker for BD-D among patients in depressive episodes.Our results suggest INPP4 A may be involved in the pathogenesis of depression.