Loss of tumor necrosis factor (TNF)‐receptor 1 and TNF‐receptor 2 partially replicate effects of TNF deficiency on dendritic spines of granule cells in mouse dentate gyrus. Issue 2 (11th October 2022)

• Record Type: Journal Article
• Authors: Smilovic, Dinko; Rietsche, Michael; Fellenz, Meike; Drakew, Alexander; Vuksic, Mario; Deller, Thomas
• Is Part Of: Journal of comparative neurology. Volume 531:Issue 2(2023)
• Page Start: 281
• Page End: 293
• Publication Date: 2022-10-11
• Subjects: homeostasis -- cytokine -- synaptopodin -- synaptic plasticity -- synapse; Comparative neurobiology -- Periodicals; Neurology -- Periodicals; 616
• DOI: 10.1002/cne.25424
• Languages: English
• ISSNs: 0021-9967

Abstract

Abstract: The cytokine tumor necrosis factor (TNF) is involved in the regulation of physiological and pathophysiological processes in the central nervous system. In previous work, we showed that mice lacking constitutive levels of TNF exhibit a reduction in spine density and changes in spine head size distribution of dentate granule cells. Here, we investigated which TNF‐receptor pathway is responsible for this phenotype and analyzed granule cell spine morphology in TNF‐R1‐, TNF‐R2‐, and TNF‐R1/R2‐deficient mice. Single granule cells were filled with Alexa568 in fixed hippocampal brain slices and immunostained for the actin‐modulating protein synaptopodin (SP), a marker for strong and stable spines. An investigator blind to genotype investigated dendritic spines using deconvolved confocal image stacks. Similar to TNF‐deficient mice, TNF‐R1 and TNF‐R2 mutants showed a decrease in the size of small spines (SP−negative) with TNF‐R1/R2‐KO mice exhibiting an additive effect. TNF‐R1 mutants also showed an increase in the size of large spines (SP−positive), mirroring the situation in TNF‐deficient mice. Unlike the TNF‐deficient mouse, none of the TNF‐R mutants exhibited a reduction in their granule cell spine densities. Since TNF tunes the excitability of networks, lack of constitutive TNF reduces network excitation. This may explain why we observed alterations in spine head size distributions in TNF‐ and TNF‐R‐deficient granule cells. The changes in spine density observed in the TNF‐deficient mouse could not be linked to canonical TNF‐R‐signaling. Instead, noncanonical pathways or unknown developmental functions of TNF may cause this phenomenon. Abstract : Hippocampal granule cells of adult mice lacking canonical TNF‐Rs were filled with Alexa568 and immunolabeled for Synaptopodin. Morphometric analysis of their spines revealed that TNF‐R mutants partially replicate changes previously reported for TNF‐deficient mice. Since TNF tunes network excitability via TNF‐Rs, TNF deficiency and altered TNF‐R‐signaling may cause morphological spine changes.