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The Journal of Neuroscience, September 20, 2006, 26(38):9703-9712; doi:10.1523/JNEUROSCI.2723-06.2006

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Development/Plasticity/Repair
Tumor Necrosis Factor Receptor 1 Is a Negative Regulator of Progenitor Proliferation in Adult Hippocampal Neurogenesis

Robert E. Iosif,^1,4 Christine T. Ekdahl,^1,4 Henrik Ahlenius,^3,4 Cornelis J. H. Pronk,^2,4 Sara Bonde,^1,4 Zaal Kokaia,^3,4 Sten-Eirik W. Jacobsen,^2,4 and Olle Lindvall^1,4

¹Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, ²Hematopoietic Stem Cell Laboratory, and ³Laboratory of Neural Stem Cell Biology, Section of Restorative Neurology, Stem Cell Institute, University Hospital, SE 221 84 Lund, Sweden, and ⁴Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, SE 221 84 Lund, Sweden

Correspondence should be addressed to Olle Lindvall, Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, Lund University Hospital, 221 84 Lund, Sweden. Email: olle.lindvall{at}med.lu.se

Tumor necrosis factor- (TNF-) is a proinflammatory cytokine, acting through the TNF-R1 and TNF-R2 receptors. The two receptors have been proposed to mediate distinct TNF- effects in the CNS, TNF-R1 contributing to neuronal damage and TNF-R2 being neuroprotective. Whether TNF- and its receptors play any role for neurogenesis in the adult brain is unclear. Here we used mouse models with loss of TNF-R1 and TNF-R2 function to establish whether signaling through these receptors could influence hippocampal neurogenesis in vivo under basal conditions, as well as after status epilepticus (SE), which is associated with inflammation and elevated TNF- levels. Notably, in the intact brain, the number of new, mature hippocampal neurons was elevated in TNF-R1^–/– and TNF-R1/R2^–/– mice, whereas no significant changes were detected in TNF-R2^–/– mice. Also after SE, the TNF-R1^–/– and TNF-R1/R2^–/– mice produced more new neurons. In contrast, the TNF-R2^–/– mice showed reduced SE-induced neurogenesis. Cell proliferation in the dentate subgranular zone was elevated in TNF-R1^–/– and TNF-R1/R2^–/– mice both under basal conditions and after SE. The TNF-R2^–/– mice either showed no change or minor decrease of cell proliferation. TNF-R1 and TNF-R2 receptors were expressed by hippocampal progenitors, as assessed with reverse transcription-PCR on sorted or cultured cells and immunocytochemistry on cultures. Our data reveal differential actions of TNF-R1 and TNF-R2 signaling in adult hippocampal neurogenesis and identify for the first time TNF-R1 as a negative regulator of neural progenitor proliferation in both the intact and pathological brain.

Key words: TNF receptors; stem cells; neurogenesis; status epilepticus; hippocampus; inflammation

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Received March 2, 2006; revised Aug. 14, 2006; accepted Aug. 15, 2006.

Correspondence should be addressed to Olle Lindvall, Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, Lund University Hospital, 221 84 Lund, Sweden. Email: olle.lindvall{at}med.lu.se

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