Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain - PubMed (original) (raw)

Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain

C J Heyser et al. Proc Natl Acad Sci U S A. 1997.

Abstract

Inflammation with expression of interleukin 6 (IL-6) in the brain occurs in many neurodegenerative disorders. To better understand the role of IL-6 in such disorders, we examined performance in a learning task in conjunction with molecular and cellular neuropathology in transgenic mice that express IL-6 chronically from astrocytes in the brain. Transgenic mice exhibited dose- and age-related deficits in avoidance learning that closely corresponded with specific progressive neuropathological changes. These results establish a link between the central nervous system expression of IL-6, inflammatory neurodegeneration, and a learning impairment in transgenic mice. They suggest a critical role for a proinflammatory cytokine in the cognitive deficits and associated neuroinflammatory changes that have been documented in neurodegenerative diseases such as Alzheimer disease and AIDS.

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Figures

Figure 1

Figure 1

Performance of GFAP-IL6 transgenic mice in a discriminated avoidance learning task. (a) Correct avoidances (mean ± SE) on acquisition (3 months of age) and subsequent retests at 6 and 12 months of age for nontransgenic (+/+) (n = 8), heterozygous GFAP-IL6 (+/tg) (n = 10), and homozygous GFAP-IL6 (tg/tg) mice (n = 7). Homozygous mice were significantly different from controls throughout the study and heterozygous mice tested at 3 and months of age. (b) Errors (mean ± SE) on acquisition and subsequent retests for nontransgenic and transgenic mice. (c) Escape latency (mean ± SE) on acquisition and subsequent retests for nontransgenic and transgenic mice.

Figure 2

Figure 2

Quantitative analysis of neurodegeneration (a) and gliosis (b) in GFAP-IL6 transgenic mice. A total of 17 mice were analyzed for selected markers utilized to assess the severity of the cellular neuropathology. GFAP-IL6 mice from both age groups were significantly different from nontransgenic controls on measures of MAP2-IR, parvalbumin-IR, and GFAP-IR. A significant loss of SYN-IR was observed in 3-month-old homozygous (tg/tg) transgenic mice and in both groups of 12-month-old transgenic mice when compared with controls, but not in 3-month-old heterozygous (+/tg) transgenic mice. The loss of calbindin-IR neurons and more intense microgliosis observed in 3-month-old heterozygous, and 12-month-old heterozygous and homozygous GFAP-IL6 mice, was significantly different from controls. Three-month-old heterozygous mice did not differ from controls on these measures. All values were expressed as percent increase or loss compared with age matched controls (mean ± SE). ∗, Significantly different from controls (P < 0.01). ∗∗, Twelve-month-old heterozygous mice were significantly different from 3-month-old heterozygous mice (P < 0.01).

Figure 3

Figure 3

Alterations in calbindin immunoreactivity in GFAP-IL6 transgenic mice. Low-power view of a 3-month-old (no differences were observed between 3- and 12-month-old nontransgenic mice) nontransgenic mouse (a) and a 3-month-old heterozygous GFAP-IL6 transgenic mouse (b) shows strong immunoreactivity in neocortical areas and in hippocampal interneurons (as indicated by the arrow). The molecular layer (ML) and mossy fiber bundle (MF) also displayed intense calbindin immunoreactivity while the pyramidal cell layer (PL) neuropil was mildly labeled. In contrast, a 12-month-old heterozygous GFAP-IL6 transgenic mouse (c) shows decreased calbindin immunoreactivity in the neocortex and hippocampus. Higher-power view of nontransgenic (d) and a 3-month-old heterozygous GFAP-IL6 transgenic mouse (e) shows strong immunoreactivity associated with neocortical interneurons in layers 2–5. The neuropil in layers 1–3 and layer 5 show a moderate level of immunostaining. In contrast, a 12-month-old heterozygous GFAP-IL6 transgenic mouse (f) shows a widespread decrease in calbindin-IR neurons in all layers of the neocortex. [Bars = 1 mm (c) and 0.1 mm (f).]

Figure 4

Figure 4

Molecular pathological alterations in the brains of GFAP-IL6 transgenic mice. (a) RNase protection assay of poly(A)+-enriched RNA isolated from the brain of nontransgenic (+/+), heterozygous GFAP-IL6 (+/tg), or homozygous (tg/tg) GFAP-IL6 transgenic mice. (b) While cerebral expression of the ICAM-1, Mac-1, EB22/5.3, and GFAP genes was increased in GFAP-IL6 mice, quantitative analysis revealed a marked difference in the levels of expression of the Mac-1 and EB22/5.3 genes between heterozygous and homozygous GFAP-IL6 mice at 3 months but not at 12 months of age. ∗, For ICAM-1, a value of 1 arbitrary unit was assigned to the 3-month-old control group because there was no detectable ICAM-1 signal in these mice.

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