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

Minna Yli-Karjanmaa, Kathrine Solevad Larsen, Christina Dühring Fenger, Lotte Kellemann Kristensen, Nellie Anne Martin, Peter Toft Jensen, Alexandre Breton, Lubov Nathanson, Pernille Vinther Nielsen, Minna Christiansen Lund, Stephanie Lindeman Carlsen, Jan Bert Gramsbergen, Bente Finsen, Jane Stubbe, Lars Henrik Frich, Helen Stolp, Roberta Brambilla, Daniel Clive Anthony, Morten Meyer, Kate Lykke Lambertsen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalBrain, Behavior, and Immunity
DOIs
StateAccepted/In press - Jan 1 2019

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Microglia
Cerebral Cortex
Tumor Necrosis Factor-alpha
Neurons
Cell Count
Inbred C57BL Mouse
Frizzled Receptors
Proteins
Neocortex
Neurogenesis
Dentate Gyrus
Bromodeoxyuridine

Keywords

  • Cytokines
  • Neurogenesis
  • TNF inhibitors

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Cite this

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex. / Yli-Karjanmaa, Minna; Larsen, Kathrine Solevad; Fenger, Christina Dühring; Kristensen, Lotte Kellemann; Martin, Nellie Anne; Jensen, Peter Toft; Breton, Alexandre; Nathanson, Lubov; Nielsen, Pernille Vinther; Lund, Minna Christiansen; Carlsen, Stephanie Lindeman; Gramsbergen, Jan Bert; Finsen, Bente; Stubbe, Jane; Frich, Lars Henrik; Stolp, Helen; Brambilla, Roberta; Anthony, Daniel Clive; Meyer, Morten; Lambertsen, Kate Lykke.

In: Brain, Behavior, and Immunity, 01.01.2019.

Research output: Contribution to journalArticle

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 2019, 'TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex', Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2019.08.195
Yli-Karjanmaa, Minna ; Larsen, Kathrine Solevad ; Fenger, Christina Dühring ; Kristensen, Lotte Kellemann ; Martin, Nellie Anne ; Jensen, Peter Toft ; Breton, Alexandre ; Nathanson, Lubov ; Nielsen, Pernille Vinther ; Lund, Minna Christiansen ; Carlsen, Stephanie Lindeman ; Gramsbergen, Jan Bert ; Finsen, Bente ; Stubbe, Jane ; Frich, Lars Henrik ; Stolp, Helen ; Brambilla, Roberta ; Anthony, Daniel Clive ; Meyer, Morten ; Lambertsen, Kate Lykke. / TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex. In: Brain, Behavior, and Immunity. 2019.
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abstract = "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 na{\"i}ve 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.",
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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

AU - Larsen, Kathrine Solevad

AU - Fenger, Christina Dühring

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 - Carlsen, Stephanie Lindeman

AU - Gramsbergen, Jan Bert

AU - Finsen, Bente

AU - Stubbe, Jane

AU - Frich, Lars Henrik

AU - Stolp, Helen

AU - Brambilla, Roberta

AU - Anthony, Daniel Clive

AU - Meyer, Morten

AU - Lambertsen, Kate Lykke

PY - 2019/1/1

Y1 - 2019/1/1

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

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