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Organotypic Slice Cultures for Studies of Postnatal Neurogenesis
Published on: March 4, 2015
Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure
Keyu Chen1,2, Dihan Lu1,2, Xiaoyu Yang1
1Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Insights
Low-dose Propofol anesthesia may enhance spatial cognition in developing brains by boosting neurogenesis and mitochondrial function. This suggests potential benefits for pediatric use, contrary to previous concerns.
Area of Science:
- Neuroscience
- Developmental Biology
- Anesthesiology
Background:
- Pediatric anesthetic use raises concerns regarding neurodevelopmental effects.
- Low-dose Propofol's impact on developing brains requires urgent investigation.
Purpose of the Study:
- To investigate the neuronal effects of low-dose Propofol on the developing brain.
- To clarify the cognitive and cellular impacts of neonatal Propofol exposure.
Main Methods:
- Neonatal mice exposed to low-dose/high-dose Propofol underwent behavioral testing.
- Neurogenesis was assessed in hippocampal and neural stem cells (NSCs).
- Transcriptome and metabolism analyses (snRNA-seq, bulk RNA-seq) identified key pathways, with PGC-1α modulation confirmed using RNA interference and viral vectors.
Main Results:
- Low-dose Propofol exposure enhanced spatial cognitive ability in mice.
- Neurogenesis was significantly activated in both hippocampal and cultured NSCs.
- Mitochondrial oxidative phosphorylation (OXPHOS) levels increased, with PGC-1α upregulation identified as a key mechanism.
Conclusions:
- Low-dose Propofol alters mitochondrial function, enhancing hippocampal neurogenesis.
- Findings suggest low-dose Propofol may be safe and potentially beneficial for pediatric use.
- This study highlights a novel mechanism involving PGC-1α and OXPHOS in Propofol's neurodevelopmental effects.
Background:
Developing brain is highly plastic and can be easily affected. Growing pediatric usage of anesthetics during painless procedures has raised concerns about the effect of low-dose anesthetics on neurodevelopment. It is urgent to ascertain the neuronal effect of low-dose Propofol, a widely used anesthetic in pediatrics, on developing brains.
Methods:
The behavioral tests after neonatal exposure to low-dose/high-dose Propofol in mice were conducted to clarify the cognitive effect. The nascent cells undergoing proliferation and differentiation stage in the hippocampus and cultured neural stem cells (NSCs) were further identified. In addition, single-nuclei RNA sequencing (snRNA-seq), NSCs bulk RNA-seq, and metabolism trials were performed for pathway investigation. Furthermore, small interfering RNA and stereotactic adenovirus injection were, respectively, used in NSCs and hippocampal to confirm the underlying mechanism.
Results:
Behavioral tests in mice showed enhanced spatial cognitive ability after being exposed to low-dose Propofol. Activated neurogenesis was observed both in hippocampal and cultured NSCs. Moreover, transcriptome analysis of snRNA-seq, bulk RNA-seq, and metabolism trials revealed a significantly enhanced oxidative phosphorylation (OXPHOS) level in NSCs. Furthermore, PGC-1α, a master regulator in mitochondria metabolism, was found upregulated after Propofol exposure both in vivo and in vitro. Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis.
Conclusions:
Taken together, this study demonstrates a novel alteration of mitochondrial function in hippocampal neurogenesis after low-dose Propofol exposure, suggesting the safety, even potentially beneficial effect, of low-dose Propofol in pediatric use.
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