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. 2019 Oct 10;14(10):e0223509.
doi: 10.1371/journal.pone.0223509. eCollection 2019.

Isoflurane mediated neuropathological and cognitive impairments in the triple transgenic Alzheimer's mouse model are associated with hippocampal synaptic deficits in an age-dependent manner

Donald J Joseph  1 , Chunxia Liu  1   2 , Jun Peng  1   3 , Ge Liang  1 , Huafeng Wei  1
Affiliations

Isoflurane mediated neuropathological and cognitive impairments in the triple transgenic Alzheimer's mouse model are associated with hippocampal synaptic deficits in an age-dependent manner

Donald J Joseph et al. PLoS One. .

Abstract

Many in vivo studies suggest that inhalational anesthetics can accelerate or prevent the progression of neuropathology and cognitive impairments in Alzheimer Disease (AD), but the synaptic mechanisms mediating these ambiguous effects are unclear. Here, we show that repeated exposures of neonatal and old triple transgenic AD (3xTg) and non-transgenic (NonTg) mice to isoflurane (Iso) distinctly increased neurodegeneration as measured by S100β levels, intracellular Aβ, Tau oligomerization, and apoptotic markers. Spatial cognition measured by reference and working memory testing in the Morris Water Maze (MWM) were altered in young NonTg and 3xTg. Field recordings in the cornu ammonis 1 (CA1) hippocampus showed that neonatal control 3xTg mice exhibited hypo-excitable synaptic transmission, reduced paired-pulse facilitation (PPF), and normal long-term potentiation (LTP) compared to NonTg controls. By contrast, the old control 3xTg mice exhibited hyper-excitable synaptic transmission, enhanced PPF, and unstable LTP compared to NonTg controls. Repeated Iso exposures reduced synaptic transmission and PPF in neonatal NonTg and old 3xTg mice. LTP was normalized in old 3xTg mice, but reduced in neonates. By contrast, LTP was reduced in old but not neonatal NonTg mice. Our results indicate that Iso-mediated neuropathologic and cognitive defects in AD mice are associated with synaptic pathologies in an age-dependent manner. Based on these findings, the extent of this association with age and, possibly, treatment paradigms warrant further study.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Isoflurane increased amyloid burden in the hippocampus of neonatal and old 3xTg-AD mice.
A) Timeline of the experimental plan, with arrows indicating the start of each experimental paradigm. Representative micrographs of 6E10 labeling in the CA1 region of the hippocampus of neonatal (B) and old (C) NonTg or 3xTg-AD mice following repeated sham or Iso exposures. Quantitative analysis of 6E10 positive cells in neonates (D) and old mice (E) mice. Statistical significance indicated with asterisks: ***p<0.001. N = 4 animals per group. Scale bar is 100μm.
Fig 2
Fig 2. Isoflurane selectively worsened Tau pathology in old 3xTg-AD mice and S100β release in neonatal NonTg mice.
Representative micrographs of AT180 positive cells in the CA1 region of the hippocampus of neonatal (A) and old (B) NonTg or 3xTg-AD mice following repeated sham or Iso exposures. Quantitative analysis of AT180 positive cells in the CA1 hippocampus of neonates (C) and old mice (D). Plasma level of S100β in neonates (E) and old mice (F). Statistical significance indicated with asterisks: ***p<0.001. N = 4 animals per group and counts are given as cells/mm2. Scale bar is 100μm.
Fig 3
Fig 3. Isoflurane selectively increased the expression level of apoptotic markers in neonates.
Representative Western blotting images of caspase 9, caspase 12, Bax, and BCL-2 from neonates (A) and old mice (B). Densitometry analysis of the caspase 9 (C), caspase 12 (D), Bax/BCL-2 (E) bands relative to their respective β-actin loading control band in neonates. Densitometry analysis of the caspase 9 (G), caspase 12 (H), Bax/BCL-2 (I) bands relative to their respective β-actin loading control band in the old mice. Statistical significance indicated with asterisks: **p<0.01 and ***p<0.001. N ≥8 animals per group and counts are given as cells/mm2. Scale bar is 100μm.
Fig 4
Fig 4. Isoflurane altered distinct spatial learning paradigms in young and old 3xTg-AD and NonTg mice.
Latency to find the submerged platform in the reference learning of the MWM test during 5 consecutive days after repeated exposures of neonates (A) and old mice (B). Quantitative analysis of short-term (C) and long term (E) probe tests in neonates. Analysis of short-term (D) and long term (F) probe tests old mice. Time saved in short-term trial-dependent working memory paradigm in neonates (G) and old mice (H). Quantitative analysis of time saved during long-term trial-dependent working memory paradigm in neonates (I) and old mice (J). Motor function measured by the accelerated Rotarod paradigm was not altered by repeated Iso exposures in both neonatal (K) and old (L) mice. Statistical significance indicated with the following symbols: *p<0.05; **, ## p<0.01, ***, ###p<0.001. Statistical analyses denoted by # represent comparisons between sham and Iso treated 3xTg-AD mice and those denoted by * compared sham treated 3xTg and NonTg mice. N≥14 animals per group.
Fig 5
Fig 5. Repeated in vivo isoflurane exposures differentially altered basal synaptic transmission in NonTg and 3xTg-AD mice.
(A) Representative traces of CA1 field EPSPs recorded in response to SC stimulations on acute slices from sham- or Iso-treated neonatal NonTg (Top traces) and 3xTg-AD (Bottom traces) mice. (B) Representative traces of CA1 field EPSPs recorded as in panel A on acute slices from sham- or Iso-treated old NonTg (Top traces) and 3xTg-AD (Bottom traces) mice. Quantitative analysis of Input-output generated by plotting mean fEPSP slope to increasing current intensities in neonatal (C) and old mice (D). Statistical significance indicated with the following symbols: *,^p<0.05; **, ## p<0.01, ***, ###p<0.001. Statistical analyses denoted by # represent comparisons between sham- and Iso-treated NonTg mice and those denoted by * compared sham-treated 3xTg and NonTg mice. Statistical analyses denoted by ^ represent comparisons between sham- and Iso-treated old NonTg mice. N≥8 animals and ≥16 slices per group.
Fig 6
Fig 6. Paired-pulse ratio is differentially altered Iso exposures.
(A) Representative traces of paired CA1 field EPSPs recorded at various inter-stimulus intervals (ISI) on acute slices from sham- and Iso-treated neonatal NonTg (Top traces) and 3xTg-AD (Bottom traces) mice. (B) Representative traces of paired-pulse CA1 field EPSPs recorded as in panel A on acute slices from old NonTg (Top traces) and 3xTg-AD (Bottom traces) mice. Quantitative analysis of fEPSP slope PPR (Pulse 2/Pulse 1) in neonatal (C) and old mice (D). Statistical significance indicated with the following symbols: **, ## p<0.01, ***, ###p<0.001. Statistical analyses denoted by # represent comparisons between sham- and Iso-treated NonTg mice and those denoted by * compared sham-treated 3xTg and NonTg mice. N≥8 animals and ≥16 slices per group.
Fig 7
Fig 7. Repeated in vivo isoflurane exposures differentially altered LTP in NonTg and 3xTg-AD mice.
(A) Representative traces of CA1 field EPSPs recorded in response to SC stimulations before and after LTP induction on acute slices from sham- and Iso-treated neonatal NonTg (Top traces) and 3xTg-AD (Bottom traces) mice. (B) Representative traces of CA1 field EPSPs recorded as in panel A on acute slices from old NonTg (Top traces) and 3xTg-AD (Bottom traces) mice before and after LTP induction. (C) Normalized fEPSP slope before and after LTP induction (200Hz, 500ms) in sham- and iso-treated neonatal (C) and old (D) mice. (E) Quantitative analysis of the first 10 min of fEPSP slope following LTP induction on acute slices from sham and Iso-treated neonatal (E) and old (F) mice. Statistical significance indicated with the following symbols: *p<0.05; **p<0.01, ***p<0.001. N≥8 animals and ≥16 slices per group.
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References

    1. Bohnen N, Warner MA, Kokmen E, Kurland LT. Early and midlife exposure to anesthesia and age of onset of Alzheimer's disease. Int J Neurosci. 1994;77(3–4):181–5. 10.3109/00207459408986029 . - DOI - PubMed
    1. Gasparini M, Vanacore N, Schiaffini C, Brusa L, Panella M, Talarico G, et al. A case-control study on Alzheimer's disease and exposure to anesthesia. Neurol Sci. 2002;23(1):11–4. 10.1007/s100720200017 . - DOI - PubMed
    1. Lee TA, Wolozin B, Weiss KB, Bednar MM. Assessment of the emergence of Alzheimer's disease following coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. J Alzheimers Dis. 2005;7(4):319–24. . - PubMed
    1. Chen CW, Lin CC, Chen KB, Kuo YC, Li CY, Chung CJ. Increased risk of dementia in people with previous exposure to general anesthesia: a nationwide population-based case-control study. Alzheimers Dement. 2014;10(2):196–204. 10.1016/j.jalz.2013.05.1766 . - DOI - PubMed
    1. Zuo C, Zuo Z. Spine Surgery under general anesthesia may not increase the risk of Alzheimer's disease. Dement Geriatr Cogn Disord. 2010;29(3):233–9. 10.1159/000295114 - DOI - PMC - PubMed

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