Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring

Abstract

Maternal sevoflurane exposure during pregnancy is associated with increased risk for behavioral deficits in offspring. Several studies indicated that neurogenesis abnormality may be responsible for the sevoflurane-induced neurotoxicity, but the concrete impact of sevoflurane on fetal brain development remains poorly understood. We aimed to investigate whether maternal sevoflurane exposure caused learning and memory impairment in offspring through inducing abnormal development of the fetal prefrontal cortex (PFC). Pregnant mice at gestational day 15.5 received 2.5% sevoflurane for 6 h. Learning function of the offspring was evaluated with the Morris water maze test at postnatal day 30. Brain tissues of fetal mice were subjected to immunofluorescence staining to assess differentiation, proliferation, and cell cycle dynamics of the fetal PFC. We found that maternal sevoflurane anesthesia impaired learning ability in offspring through inhibiting deep-layer immature neuron output and neuronal progenitor replication. With the assessment of cell cycle dynamics, we established that these effects were mediated through cell cycle arrest in neural progenitors. Our research has provided insights into the cell cycle-related mechanisms by which maternal sevoflurane exposure can induce neurodevelopmental abnormalities and learning dysfunction and appeals people to consider the neurotoxicity of anesthetics when considering the benefits and risks of nonobstetric surgical procedures.

Usp11 controls cortical neurogenesis and neuronal migration through Sox11 stabilization

“…Nevertheless, impairment of layer 6 neurogenesis has been linked to learning/memory deficit. For instance, sevoflurane exposure of pregnant mice causes layer 6 neurogenesis defect and learning/memory abnormality ( 30 ). In addition, the layer 6 marker Tbr1 is essential for specifying layer 6 identity ( 31 ), and its heterozygous variants have been found in patients with autism spectrum disorder ( 32 ).…”

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

“…The mPFC development is a continuous process and retains its neuroplasticity throughout the life 24 . Thus, sevoflurane could induce neurodevelopmental diseases by regulating synaptogenesis and synaptic development in the mPFC 36 , which suggests that mPFC neurons are vulnerable to sevoflurane-induced neurotoxicity. Indeed, our study found that neonatal exposure to sevoflurane-induced ADHD-like impulsive behavior at the adult stage through over-activating the mPFC excitatory neurons ( Fig.…”

The association between attention deficit hyperactivity disorder and general anaesthesia ‐ a narrative review

“…Ketamine anaesthesia interrupts the transfer of information between cortical areas in Rhesus monkeys and humans [43,44]. Prenatal anaesthesia, with ketamine or sevoflurane, causes neuronal loss and dysplasia of pyramidal neurons in the prefrontal cortex of rat pups [45,46]. Stimulation of the same cells alleviates ADHD signs [33].…”

“…Clinical studies [7][8][9][10][11][12][13][14][15] Animal studies [16][17][18][19][20] Neural molecular mechanisms Dopamine receptor [6,[21][22][23][24][25][26][27][28] N-methyl-D-aspartic acid receptor [29][30][31][32][33][34][35][36] Brain-derived neurotrophic factor [37][38][39][40][41] Neural network mechanisms Prefrontal cortex [33,[42][43][44][45][46][47][48][49][50] Synaptogenesis [7,33,[47][48][49]…”