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Dual Electrophysiological Recordings of Synaptically-evoked Astroglial and Neuronal Responses in Acute Hippocampal Slices
Published on: November 26, 2012
Hippocampal microglial activation triggers a neurotoxic-specific astrocyte response and mediates etomidate-induced
Dongliang Li1, Mingming Chen2, Tao Meng1
1Department of Anesthesiology, Qilu Hospital of Shandong University, Ji'nan, 250012, China.
Background:
Accumulating evidence has highlighted the importance of microglial and astrocyte responses in the pathological development of postoperative cognitive dysfunction (POCD). However, the mechanisms involved are not well understood.
Methods:
A perioperative neurocognitive disorders (PND) mouse model was generated by administering etomidate, and cognitive function was assessed using the Morris water maze and novel object recognition tests. Excitatory and inhibitory postsynaptic currents were recorded to analyze neuronal activity. In addition, microglia and astrocytes were isolated by magnetic-activated cell sorting, and genes that were activated in these cells were identified using quantitative polymerase chain reaction.
Results:
We observed dramatic cognitive impairment at 1 and 3 weeks after etomidate was administered to 18 month-old mice. Microglia and astrocytes isolated from the hippocampus showed significant microglial activation during the early pathological stage (i.e., 1 week after etomidate injection) and an A1-specific astrocyte response during the late pathological stage (i.e., 3 weeks after etomidate injection). Furthermore, when microglia were eliminated before etomidate was injected, the A1-specific astrocyte activation response was significantly reduced, and cognitive function improved. However, when microglia were eliminated after etomidate application, astrocyte activation and cognitive function were not significantly altered. In addition, activating microglia immediately after a sedative dose of etomidate was injected markedly increased A1-specific astrocyte activation and cognitive dysfunction.
Conclusions:
A1-specific astrocyte activation is triggered by activated microglia during the initial pathological stage of PND and induces long-term synaptic inhibition and cognitive deficiencies. These results improve our understanding of how PND develops and may suggest therapeutic targets.
Insights
Activated microglia trigger A1-specific astrocyte responses, leading to cognitive decline in postoperative neurocognitive disorders (PND). Targeting this pathway may offer new therapeutic strategies for PND.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Postoperative cognitive dysfunction (POCD) involves microglial and astrocyte responses.
- Mechanisms underlying POCD pathogenesis remain unclear.
Purpose of the Study:
- Investigate the role of microglia and astrocytes in etomidate-induced perioperative neurocognitive disorders (PND) in aged mice.
- Elucidate the temporal relationship between microglial activation, astrocyte response, and cognitive impairment.
Main Methods:
- Established a PND mouse model using etomidate in aged mice.
- Assessed cognitive function via behavioral tests (Morris water maze, novel object recognition).
- Analyzed neuronal activity, isolated microglia/astrocytes, and quantified gene expression.
Main Results:
- Etomidate induced significant cognitive impairment in aged mice.
- Early microglial activation preceded late A1-specific astrocyte activation and cognitive deficits.
- Eliminating microglia early ameliorated astrocyte activation and improved cognition.
- Activating microglia post-sedation exacerbated astrocyte activation and cognitive dysfunction.
Conclusions:
- Microglia initiate A1-specific astrocyte activation in early PND stages.
- This astrocyte response leads to synaptic inhibition and long-term cognitive deficits.
- Findings suggest microglia-astrocyte interactions as a therapeutic target for PND.
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