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,Ge Liang,Huafeng Wei,Chunxia Liu,Jun Peng,Stephen D Ginsberg

doi:10.1371/journal.pone.0223509

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.

Highlights

Recent epidemiological evidence indicates that life experiences, including surgeries and multiple exposures to general anesthetics, are associated with Alzheimer Disease (AD) [1,2,3,4,5]
Accumulating evidence in the literature suggests that exposures of various AD mouse models to anesthetics can lead to immediate cellular pathologies followed by a diverse array of cognitive impairments later in life [9]
We tested the hypothesis that repeated exposures of the 3xTg mice to Iso will lead to immediate cellular pathologies and diverse cognitive changes that are associated with different aspects of synaptic functions

Summary

Introduction

Recent epidemiological evidence indicates that life experiences, including surgeries and multiple exposures to general anesthetics, are associated with AD [1,2,3,4,5]. Emerging evidence from many AD mouse models suggests that general anesthetics impinge on neuropathology and cognitive functions[9]. Many in vivo findings suggest that exposure to general anesthetics might exacerbate neuropathology in AD mice [10, 11]. The effects of general anesthetics on cognition are ambiguous, with inhalational anesthetics appear capable of improving cognition while capable of exacerbating and mitigate the progression of its impairments in AD mice [9, 12,13,14,15]

Methods

Results

Discussion

Conclusion