Repeated Exposure to Sevoflurane Impairs GABAergic Neuronal Development and Social Cognitive Function in the Hippocampal CA2 Region of Mice

Academic Background

Approximately 1.5 million infants and young children undergo medical procedures requiring general anesthesia annually, with sevoflurane being widely used in pediatric anesthesia. However, increasing clinical and animal studies suggest that exposure to sevoflurane during infancy may lead to long-term neurocognitive deficits and behavioral impairments, particularly social behavioral disorders. Although previous research has linked sevoflurane exposure to neuronal apoptosis, altered synaptic plasticity, and neurotransmitter disturbances, the specific neurophysiological mechanisms remain unclear. The hippocampal CA2 region (cornu ammonis area 2 subregion, CA2) is a critical center for encoding social information. The researchers hypothesized that sevoflurane exposure might disrupt neuronal activity in the CA2 region, leading to social behavioral disorders.

Source of the Paper

This paper was co-authored by Shuai Wang, Zijie Li, Xin Liu, Shiyue Fan, Xuejiao Wang, Jianjun Chang, Ling Qin, and Ping Zhao, affiliated with the Department of Anesthesiology at Shengjing Hospital of China Medical University, the School of Life Sciences at China Medical University, and the Department of Breast Surgery at the Cancer Hospital of Dalian University of Technology. The paper was published on August 13, 2024, in the British Journal of Anaesthesia, titled Repeated postnatal sevoflurane exposure impairs social recognition in mice by disrupting GABAergic neuronal activity and development in hippocampus.

Research Process and Results

Research Process

1. Animal Model Construction:
   The study used C57BL/6 mice, divided into a control group (ctrl) and a sevoflurane-exposed group (sevo). The sevoflurane group was exposed to 3% sevoflurane and 60% oxygen for 2 hours on postnatal days 6, 8, and 10 (PND 6, 8, 10), while the control group was exposed to 60% oxygen alone.

2. Behavioral Testing:
   At PND 60-65, the researchers conducted a series of behavioral tests, including the open field test (OFT), Y-maze test, sociability test, and social preference test, to assess the social cognitive function of the mice.

3. Electrophysiological Recordings:
   Multi-channel electrodes were used to record neuronal activity in the CA2 region during social interactions. Optogenetic methods were employed to distinguish between GABAergic and non-GABAergic neuronal activity patterns.

4. Histological Analysis:
   Immunofluorescence staining and RNA sequencing (RNA-seq) were used to analyze the density, dendritic complexity, and expression levels of key transcription factors in GABAergic neurons in the CA2 region.

Key Results

1. Impaired Social Cognitive Function:
   Sevoflurane-exposed mice exhibited deficits in social novelty recognition in adulthood, particularly in the social preference test, where their ability to recognize unfamiliar mice was significantly reduced.

2. Abnormal Neuronal Activity in the CA2 Region:
   Sevoflurane exposure led to decreased synchronization of neuronal activity in the CA2 region, manifested as reduced synchronization of neuronal spiking, gamma oscillation power, and phase-locking between GABAergic spiking and gamma oscillations.

3. Impaired Development of GABAergic Neurons:
   Sevoflurane-exposed mice showed a significant reduction in the density and dendritic complexity of GABAergic neurons in the CA2 region, along with downregulated expression of transcription factors critical for GABAergic neuronal development (e.g., Arx, Lhx6, and Nkx2-1).

4. RNA Sequencing Results:
   RNA-seq analysis revealed 153 upregulated and 243 downregulated genes in the CA2 region of sevoflurane-exposed mice, with downregulated genes primarily associated with GABAergic neuron differentiation and maturation.

Conclusions and Significance

This study found that repeated exposure to sevoflurane disrupts the development of GABAergic neurons in the CA2 region by downregulating key transcription factors, leading to impaired electrophysiological function in adult GABAergic neurons and ultimately resulting in social cognitive deficits. These findings reveal a potential neuropathological mechanism underlying the long-term social recognition deficits induced by sevoflurane exposure during early development and provide new insights for clinically reducing the side effects of sevoflurane and enhancing the safety of pediatric anesthesia.

Research Highlights

1. Key Findings:
   The study is the first to reveal that sevoflurane exposure impairs social cognitive function by disrupting the development and function of GABAergic neurons in the CA2 region.

2. Methodological Innovations:
   The research combined behavioral testing, electrophysiological recordings, optogenetics, and RNA sequencing to comprehensively analyze the effects of sevoflurane exposure on CA2 neurons.

3. Clinical Implications:
   The findings provide a theoretical basis for reducing the side effects of sevoflurane in pediatric anesthesia, suggesting that future interventions could target the regulation of GABAergic neuron development to prevent or mitigate anesthesia-related neurodevelopmental disorders.

Additional Valuable Information

Although this study highlights the significant impact of sevoflurane exposure on GABAergic neurons in the CA2 region, some limitations remain. For example, the study did not explore the effects of sevoflurane exposure on other brain regions (e.g., the prefrontal cortex and amygdala), which are also involved in social behavior. Additionally, human social interactions are more complex than those of mice, and future research should further investigate the effects of sevoflurane exposure on human social behavior.