Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis

Ofra Ben Menachem-Zidon, Inbal Goshen, Tirzah Kreisel, Yair Ben Menahem, Etti Reinhartz, Tamir Ben Hur, Raz Yirmiya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

The proinflammatory cytokine interleukin-1 (IL-1) within the brain is critically involved in mediating the memory impairment induced by acute inflammatory challenges and psychological stress. However, the role of IL-1 in memory impairment and suppressed neurogenesis induced by chronic stress exposure has not been investigated before now. We report here that mice that were isolated for 4 weeks displayed a significant elevation in hippocampal IL-1β levels concomitantly with body weight loss, specific impairment in hippocampal-dependent memory, and decreased hippocampal neurogenesis. To examine the causal role of IL-1 in these effects, we developed a novel approach for long-term delivery of IL-1 receptor antagonist (IL-1ra) into the brain, using transplantation of neural precursor cells (NPCs), obtained from neonatal mice with transgenic overexpression of IL-1ra (IL-1raTG) under the glial fibrillary acidic protein promoter. Four weeks following intrahippocampal transplantation of IL-1raTG NPCs labeled with PKH-26, the transplanted cells were incorporated within the dentate gyrus and expressed mainly astrocytic markers. IL-1ra levels were markedly elevated in the hippocampus, but not in other brain regions, by 10 days and for at least 4 weeks post-transplantation. Transplantation of IL-1raTG NPCs completely rescued the chronic isolation-induced body weight loss, memory impairment, and suppressed hippocampal neurogenesis, compared with isolated mice transplanted with WT cells or sham operated. The transplantation had no effect in group-housed mice. These findings elucidate the role of IL-1 in the pathophysiology of chronic isolation and suggest that transplantation of IL-1raTG NPCs may provide a useful therapeutic procedure for IL-1-mediated memory disturbances in chronic inflammatory and neurological conditions.

Original languageAmerican English
Pages (from-to)2251-2262
Number of pages12
JournalNeuropsychopharmacology
Volume33
Issue number9
DOIs
StatePublished - Aug 2008

Bibliographical note

Funding Information:
We thank Prof. K Iverfeldt for the IL-1raTG mice. This study was supported by grants from the Israel Ministry of Health (no. 2985) and the Israel Science Foundation (Grant no. 295/07 to RY). RY is a member of the Eric Roland Center for Neurodegenerative Diseases at the Hebrew University of Jerusalem.

Keywords

  • Chronic isolation
  • Hippocampus
  • Interleukin-1
  • Memory
  • Neural precursor cell transplantation
  • Neurogenesis

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