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Sevoflurane anaesthesia induces cognitive impairment in young mice through sequential tau phosphorylation
Feng Liang1, Mengzhu Li2, Miao Xu3
1Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Background:
The volatile anaesthetic sevoflurane induces time (single or multiple exposures)-dependent effects on tau phosphorylation and cognitive function in young mice. The underlying mechanism for this remains largely undetermined.
Methods:
Mice received 3% sevoflurane for 0.5 h or 2 h daily for 3 days on postnatal day (P) 6, 9, and 12. Another group of mice received 3% sevoflurane for 0.5 h or 1.5 h (3 × 0.5) on P6. We investigated effects of sevoflurane anaesthesia on tau phosphorylation on P6 or P12 mice, on cognitive function from P31 to P37, and on protein interactions, using in vivo studies, in vitro phosphorylation assays, and nanobeam single-molecule level interactions in vitro.
Results:
An initial sevoflurane exposure induced CaMKIIα phosphorylation (132 [11]% vs 100 [6]%, P<0.01), leading to tau phosphorylation at serine 262 (164 [7]% vs 100 [26]%, P<0.01) and tau detachment from microtubules. Subsequent exposures to the sevoflurane induced GSK3β activation, which phosphorylated detached or free tau (tau phosphorylated at serine 262) at serine 202 and threonine 205, resulting in cognitive impairment in young mice. In vitro phosphorylation assays also demonstrated sequential tau phosphorylation. Nanobeam analysis of molecular interactions showed different interactions between tau or free tau and CaMKIIα or GSK3β, and between tau and tubulin at a single-molecule level.
Conclusions:
Multiple exposures to sevoflurane can induce sequential tau phosphorylation, leading to cognitive impairment in young mice, highlighting the need to investigate the underlying mechanisms of anaesthesia-induced tau phosphorylation in developing brain.
Insights
Repeated sevoflurane anesthesia in young mice causes sequential tau phosphorylation, leading to cognitive deficits. This study reveals the underlying molecular mechanisms of anesthesia-induced tau changes in the developing brain.
Area of Science:
- Neuroscience
- Anesthesiology
- Molecular Biology
Background:
- Volatile anesthetics like sevoflurane can impact brain development.
- Time-dependent effects of sevoflurane on tau phosphorylation and cognition are observed but mechanisms are unclear.
Purpose of the Study:
- To elucidate the mechanisms of sevoflurane-induced tau phosphorylation and cognitive impairment in young mice.
- To investigate the sequential nature of tau phosphorylation following repeated sevoflurane exposure.
Main Methods:
- Mice were exposed to sevoflurane at different durations and frequencies on specific postnatal days.
- Investigated tau phosphorylation, cognitive function, and protein interactions using in vivo, in vitro, and single-molecule assays.
Main Results:
- Initial sevoflurane exposure triggered CaMKIIα and tau phosphorylation (Ser262), detaching tau from microtubules.
- Subsequent exposures activated GSK3β, phosphorylating free tau (Ser202/Thr205), causing cognitive impairment.
- Single-molecule analysis revealed distinct interactions between tau, kinases, and microtubules.
Conclusions:
- Multiple sevoflurane exposures induce sequential tau phosphorylation, impairing cognitive function in young mice.
- Understanding these mechanisms is crucial for evaluating anesthesia risks in developing brains.
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