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-α may be important in brain development,as well as in regulating excitatory amino acid receptor trafficking and synaptic strength.Under the disease conditions,TNF-α levels changes by 40 folds compared to the normal conditions.However,given the large scale of TNF-α levels changes in the development of various diseases,the dose influence and the mechanisms whereby TNF-α might regulate synaptic plasticity,synaptogenesis and mood-and anxiety-associated behaviors remain unknown.Method:We studied high and low concentrations of TNF-α 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-α 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-α(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-α(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-α induced synaptogenesis.Low-dose TNF-α treatment had a potential anxiolytic effect whereas high-dose TNF-α treatment didn’t have an anxiolytic effect in the open field test and elevated plus maze test.Conclusion : TNF-α affects hippocampal synaptogenesis and new synapses formation in a dose-specific manner.TNF-α effect on synaptogenesis is mediated via activation of protein kinase C.TNF-α regulates anxiety-like behaviors in a dose-specific manner.