The Effect Of Ketamine On Neuronal Apoptosis In The Neonatal Mouse Cortex And Its Underlying Mechanism

Background:Ketamine is a general anesthetic commonly used in pediatric anesthesia.Previous studies demonstrated that ketamine could increase neuronal apoptosis in the neonatal brain.However,few studies showed whether the magnitude and characteristics of ketamine-induced neuronal apoptosis in the cerebral cortex altered with age.Furthermore,neural activity plays essential roles in the development of the brain,and impacts on the magnitude of physiological cell death.Whether and how altering neural activity during development impacts ketamine-induced apoptosis had not been previously studied.Objectives:The aim of this study is to investigate whether the magnitude,laminar pattern and cell-type specificity of ketamine-induced neuronal apoptosis in the primary somatosensory(S1)cortex was age-dependent,and whether and how neural activity influenced ketamine-induced neuronal apoptosis during the development of S1,andto examine the effect of enriched environment(EE)-rearing on ketamine-induced apoptosis.Methods:⑴ Using immunohistochemistry,we assayed the magnitude,distribution pattern and cell type specificity of ketamine-induced apoptosis in S1 cortex of mice pups at different ages;⑵Using the DREADDs method,we measured the impact of increasing or decreasing neuronal activity during development of S1 cortex on the magnitude and characteristics of ketamine-induced apoptosis;⑶Rearing mice in an enriched environment(EE)from birth,we assayed the magnitude and characteristics of ketamine-induced apoptosis in S1 cortex of EE-reared mice.Results:⑴ The magnitude of ketamine-induced neuronal apptosis in S1 cortex was age-dependent;the peak vulnerability to ketamine-induced apoptosis occurred at P5 and P7;at P12,ketamine did not increase neuronal apoptosis in S1 cortex;⑵ At P5,the majority of ketamine-induced apoptosis concentrated in layer V pyramidal neurons,and only a small proportion of apoptotic neurons were interneurons.However,at P9,most apoptotic neurons induced by ketamine concentrated in layers II-IV,and the majority of apoptotic neurons were interneurons.The characteristics of ketamine-induced apoptosis were similar with that of physiological cell death;⑶ Increase or decrease neuronal activity during the development of S1 cortex separately attenuated or augmented ketamine-induced neuronal apoptosis,and altered the cell-type specificity and magnitude of apoptosis;⑷ EE-reared mice showed reduced magnitude of both physiological cell death and ketamine-induced apoptosis in S1 cortex,and both the laminar pattern and the cell-type specificity shifted to more mature states.Conclusions:Ketamine increased neuronal apoptosis in S1 cortex following similar characteristics with the physiological cell death.The magnitude and characteristics of ketamine-induced apoptosis were age-dependent,and regulated by neuronal activity during the development of S1 cortex.Enriched environment-rearing could rescue ketamine-induced neuronal apoptosis.