TY - JOUR
T1 - TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex
AU - Yli-Karjanmaa, Minna Liisa Kyllikki
AU - Larsen, Kathrine Solevad
AU - Fenger, Christina
AU - Kristensen, Lotte Kellemann
AU - Martin, Nellie Anne
AU - Jensen, Peter Toft
AU - Breton, Alexandre
AU - Nathanson, Lubov
AU - Nielsen, Pernille Vinther
AU - Lund, Minna Christiansen
AU - Lindeman Carlsen, Stephanie
AU - Gramsbergen, Jan Bert
AU - Finsen, Bente
AU - Stubbe, Jane
AU - Frich, Lars Henrik
AU - Stolp, Helen
AU - Brambilla, Roberta
AU - anthony, Daniel
AU - Meyer, Morten
AU - Lambertsen, Kate Lykke
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Background: Although tumor necrosis factor (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. Materials and methods: To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF
−/−) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF
−/− mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the 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 WT and TNF
−/− mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. Results: TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU
+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. Conclusion: TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.
AB - Background: Although tumor necrosis factor (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. Materials and methods: To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF
−/−) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF
−/− mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the 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 WT and TNF
−/− mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. Results: TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU
+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. Conclusion: TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.
KW - Cytokines
KW - Neurogenesis
KW - TNF inhibitors
U2 - 10.1016/j.bbi.2019.08.195
DO - 10.1016/j.bbi.2019.08.195
M3 - Journal article
C2 - 31505254
SN - 0889-1591
VL - 82
SP - 279
EP - 297
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -