RESUMEN
BACKGROUND: Repeated exposure to sevoflurane during early developmental stages is a risk factor for social behavioural disorders, but the underlying neuropathological mechanisms remain unclear. As the hippocampal cornu ammonis area 2 subregion (CA2) is a critical centre for social cognitive functions, we hypothesised that sevoflurane exposure can lead to social behavioural disorders by disrupting neuronal activity in the CA2. METHODS: Neonatal mice were anaesthetised with sevoflurane 3 vol% for 2 h on postnatal day (PND) 6, 8, and 10. Bulk RNA sequencing of CA2 tissue was conducted on PND 12. Social cognitive function was assessed by behavioural experiments, and in vivo CA2 neuronal activity was recorded by multi-channel electrodes on PND 60-65. RESULTS: Repeated postnatal exposure to sevoflurane impaired social novelty recognition in adulthood. It also caused a decrease in the synchronisation of neuronal spiking, gamma oscillation power, and spike phase-locking between GABAergic spiking and gamma oscillations in the CA2 during social interaction. After sevoflurane exposure, we observed a reduction in the density and dendritic complexity of CA2 GABAergic neurones, and decreased expression of transcription factors critical for GABAergic neuronal development after. CONCLUSIONS: Repeated postnatal exposure to sevoflurane disturbed the development of CA2 GABAergic neurones through downregulation of essential transcription factors. This resulted in impaired electrophysiological function in adult GABAergic neurones, leading to social recognition deficits. These findings reveal a potential electrophysiological mechanism underlying the long-term social recognition deficits induced by sevoflurane and highlight the crucial role of CA2 GABAergic neurones in social interactions.
RESUMEN
BACKGROUND: The association between prenatal exposure to general anaesthesia for maternal surgery during pregnancy and subsequent risk of disruptive or internalising behavioural disorder diagnosis in the child has not been well-defined. METHODS: A nationwide sample of pregnant women linked to their liveborn infants was evaluated using the Medicaid Analytic eXtract (MAX, 1999-2013). Multivariate matching was used to match each child prenatally exposed to general anaesthesia owing to maternal appendectomy or cholecystectomy during pregnancy with five unexposed children. The primary outcome was diagnosis of a disruptive or internalising behavioural disorder in children. Secondary outcomes included diagnoses for a range of other neuropsychiatric disorders. RESULTS: We matched 34,271 prenatally exposed children with 171,355 unexposed children in the database. Prenatally exposed children were more likely than unexposed children to receive a diagnosis of a disruptive or internalising behavioural disorder (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.23-1.40). For secondary outcomes, increased hazards of disruptive (HR, 1.32; 95% CI, 1.24-1.41) and internalising (HR, 1.36; 95% CI, 1.20-1.53) behavioural disorders were identified, and also increased hazards of attention-deficit/hyperactivity disorder (HR, 1.32; 95% CI, 1.22-1.43), behavioural disorders (HR, 1.28; 95% CI, 1.14-1.42), developmental speech or language disorders (HR, 1.16; 95% CI, 1.05-1.28), and autism (HR, 1.31; 95% CI, 1.05-1.64). CONCLUSIONS: Prenatal exposure to general anaesthesia is associated with a 31% increased risk for a subsequent diagnosis of a disruptive or internalising behavioural disorder in children. Caution is advised when making any clinical decisions regarding care of pregnant women, as avoidance of necessary surgery during pregnancy can have detrimental effects on mothers and their children.