Intrahippocampal Transplantation of Transgenic Neural Precursor Cells Overexpressing Interleukin-1 Receptor Antagonist Blocks Chronic Isolation-Induced Impairment in Memory and Neurogenesis

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-1b levels concomitantly with body weight loss, specific impairment in hippocampaldependent 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.

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Many studies have characterised changes in neurogenesis in response to generalised inflammation (Ekdahl et al, 2003;Monje et al, 2003) and also to specific cytokines (Koo and Duman, 2008). Moreover, numerous studies have explored inflammation-mediated effects, not only on neurogenesis, but also on hippocampal-dependent memory function (Ben Menachem-Zidon et al, 2008). Other studies have focused solely on inflammation mediated effects on cognitive function independent of possible neurogenic effects (Adzovic et al, 2015;Dinel et al, 2014).…”

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

“…Therefore, in addition to IFN-a's effects on serotonin , dopamine (Felger et al, 2007), glutamate (Raison et al, 2010b), and the hypothalamic-pituitary-adrenal axis (Raison et al, 2010a), a decrease in BDNF may ultimately be the reason for the development of depression during IFN-a treatment. Related to this, social isolation decreases central BDNF, an effect which is likely mediated by the inflammatory cytokine IL1b (Barrientos et al, 2003;Ben Menachem-Zidon et al, 2008;Koo and Duman, 2008). IFN-a also appears to decrease cell proliferation in the hippocampus via increased IL-1b (Kaneko et al, 2006).…”

Repeated social defeat stress induces neuroinflammation and impairs hippocampal neurogenesis that differentially regulate mood and cognition

“…For example, chronic isolation stress has been shown to reduce neurogenesis and impair several measures of learning and memory in an IL-1 receptor dependent manner [34]. For example, mice exposed to chronic isolation stress showed increased expression of hippocampal IL1² concomitant with memory impairments, which were reversed upon transplantation of neural progenitor cells overexpressing IL-1ra (IL-1 receptor antagonist) into the hippocampus [34]. The RSD-induced inflammation and subsequent impairments could extend well beyond neurons to other cell types, such as, glial cells [25].…”

“…Cognitive impairments following stress have been previously associated with inflammation and impaired neurogenesis [34]. Therefore, given that RSD increased hippocampal IL-1² expression in the current study (Table 1), the effects of RSD on neurogenesis were determined.…”