| Experiment Id | GSE134178 | Name | TNF deficiency causes changes in the spatial organization of neurogenic zones and the number of microglia and neurons in the cerebral cortex |
| Experiment Type | transcription profiling by array | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2023-12-21 |
| description | 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 naive 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. Results: TNF deficiency initially decreased the number of proliferating cells and microglia, but subsequently 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, longterm inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of proliferating 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. We first characterized the possible effects of developmental TNF deficiency and long-term inhibition of TNF in adulthood on gene and protein expression, monoamine levels, neurogenesis, and cell composition in the brain, and on the function and permeability of the blood-brain barrier (BBB). We then investigated the effect of TNF deficiency on cognitive functions. Adult male TNF+/+ and TNF-/- brain lysates were used for RNA isolation. Isolated RNA was quality assessed using the Agilent RNA 6000 Nano Kit (Agilent Technologies, Santa Clara, CA, USA) with an Agilent 2100 bioanalyzer (Agilent Technologies). Isolated RNA was hybridized to the Affymetrix GeneChip Mouse Gene 1.0 ST Array according to the manufactorer protocol (Thermo Fisher Scientific, Waltham, MA, USA). We used the Significance Analysis of Microarray (SAM) method to identify probe sets with target in transcripts that were significantly differentially expressed between TNF+/+ and TNF-/- mice (Tusher et al., 2001). SAM analysis was performed using MultiExperimentViewer Software v. 4.5.1. (Dana- Farber Cancer Institute, Boston, MA, USA), 70 unique permutations and an s0 value selected by Tusher's method (Saeed et al., 2006; Saeed et al., 2003; Tusher et al., 2001). A false discovery rate (FDR) < 5% was considered evidence of statistical significance. |
