TNF deficiency causes changes in the spatial organization of neurogenic zones and the number of microglia and neurons in the cerebral cortex

Background: Although TNF inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. TNF is known to modulate neurogenesis by decreasing cell proliferation, increasing apoptosis of precursor cells, and impairing neuronal differentiation. TNF can also influence the formation of the hippocampus, with long-lasting effects on cognition. Materials and methods: To clarify whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the brains of E13.5, P7, and adult TNF +/+ and TNF-/- mice and measured changes in gene and protein expression and monoamine levels in adult TNF+/+ and TNF-/- mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, selective soluble TNF inhibitor XPro1595, or nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult TNF+/+ and TNF-/- mice and anti-TNF treated mice with behavioral tasks.

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Yli-Karjanmaa M, Larsen KS, Fenger CD, Kristensen LK, Martin NA, Jensen PT, Breton A, Nathanson L, Nielsen PV, Lund MC, Carlsen SL, Gramsbergen JB, Finsen B, Stubbe J, Frich LH, Stolp H, Brambilla R, Anthony DC, Meyer M, Lambertsen KL