Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis.
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-1beta 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.
Ben Menachem-Zidon
Ofra
O
Department of Psychology, The Hebrew University of Jerusalem, Department of Neurology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Goshen
Inbal
I
Kreisel
Tirzah
T
Ben Menahem
Yair
Y
Reinhartz
Etti
E
Ben Hur
Tamir
T
Yirmiya
Raz
R
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D049109:Cell Proliferation; D003213:Conditioning, Psychological / Q000502:physiology*; D000089622:Doublecortin Domain Proteins; D005239:Fear; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D009930:Organic Chemicals / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods; D013997:Time Factors
D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D009479:Neuropeptides; D009930:Organic Chemicals; C070080:PKH 26