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

Autoři: Donald J. Joseph aff001;  Chunxia Liu aff001;  Jun Peng aff001;  Ge Liang aff001;  Huafeng Wei aff001
Působiště autorů: Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America aff001;  Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China aff002;  Department of Anesthesiology, sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article


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.

Klíčová slova:

Alzheimer's disease – Anesthetics – Cognitive impairment – Mice – Mouse models – Neonates – Working memory – Long term memory


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