TNF-Alpha Regulates Functional Synaptogenesis And Anxiety-like Behaviors In A Dose Specific Manner

Background: The pro-inflammatory cytokines play an important role in modulating central nervous system(CNS)function under both physiological and pathological conditions.Physiologically low levels of TNF-? may be important in brain development,as well as in regulating excitatory amino acid receptor trafficking and synaptic strength.Under the disease conditions,TNF-? levels changes by 40 folds compared to the normal conditions.However,given the large scale of TNF-? levels changes in the development of various diseases,the dose influence and the mechanisms whereby TNF-? might regulate synaptic plasticity,synaptogenesis and mood-and anxiety-associated behaviors remain unknown.Method:We studied high and low concentrations of TNF-? regulate the formation and mechanism of new synapses and anxiety-like behaviors in hippocampal neuron and the male C57BL/6 mice by biochemical and behavioral experiments.After TNF-? treatment,synaptogensis and new synapse formation were determined by double immunofluorescent staining and western blot analysis.Anxiety-like behaviors were determined by open field test and elevated plus maze test.Results: We found that incubation of hippocampal cultures with low concentrations of TNF-?(60 pM,600pM)for one day increased the number of synaptic and synaptogensis,this increase in number of synapses sustained to 3 days.Interestingly,high concentration of TNF-?(1200pM)day also increased the number of synaptic puncta after one-day treatment,but effects on synaptogenesis did not last after three days of treatment.Inhibition of PKC activity by cherylethrine for 1 day significantly decreased TNF-? induced synaptogenesis.Low-dose TNF-? treatment had a potential anxiolytic effect whereas high-dose TNF-? treatment didn't have an anxiolytic effect in the open field test and elevated plus maze test.Conclusion : TNF-? affects hippocampal synaptogenesis and new synapses formation in a dose-specific manner.TNF-? effect on synaptogenesis is mediated via activation of protein kinase C.TNF-? regulates anxiety-like behaviors in a dose-specific manner.