Abstract
The effects of general anesthetics on inducing neuronal apoptosis during early brain development are well-documented. However, since physiological apoptosis also occurs during this developmental window, it is important to determine whether anesthesia-induced apoptosis targets the same cell population as physiological apoptosis or different cell types altogether. To provide an adequate plane of surgery, ketamine was co-administered with dexmedetomidine. The apoptotic neurons in the mouse primary somatosensory cortex (S1) were quantitated by immunohistochemistry. To explore the effect of neural activity on ketamine-induced apoptosis, the approaches of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and an environmental enrichment (EE) were performed. Ketamine-induced apoptosis in S1 is most prominent at postnatal days 5 and 7 (P5 – P7), and becomes insignificant by P12. Physiological and ketamine-induced apoptosis follow similar developmental patterns, mostly comprised of layer V pyramidal neurons at P5 and shifting to mostly layer II to IV GABAergic neurons by P9. Changes in neuronal activity induced by the DREADD system bidirectionally regulated the pattern of ketamine-induced apoptosis, with reduced activity inducing increased apoptosis and shifting the lamination pattern to a more immature form. Importantly, rearing mice in an EE significantly reduced the magnitude of ketamine-induced apoptosis and shifted its developmental pattern to a more mature form. Together, these results demonstrate that lamination pattern and cell-type dependent vulnerability to ketamine-induced apoptosis follow the physiological apoptosis pattern and are age- and activity-dependent. Naturally elevating neuronal activity is a possible method for reducing the adverse effects of general anesthesia.
Highlights
The potential adverse effects of general anesthetics on the developing brain is an area of major concern for anesthesiologists, surgeons and parents [1,2,3,4]
Since ketamine mediates its effects primarily by blocking N-Methyl-D-aspartic acid (NMDA) receptors, and the NMDA receptor antagonist MK-801 has been shown to induce apoptosis [18], we investigated the effect of neuronal activity on the ketamine-induced apoptosis using the Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system and environmental enrichment (EE)
Caspase-3 is a key mediator of apoptosis, whose cleavage and activation is often defined as the point of no return for a cell’s commitment to the cell death program [31,32,33]
Summary
The potential adverse effects of general anesthetics on the developing brain is an area of major concern for anesthesiologists, surgeons and parents [1,2,3,4]. A well-described effect of general anesthetics is inducing neuronal apoptosis [3, 8, 9, 12]. In the developing cerebral cortex, physiological apoptosis mostly occurs during the brain growth spurt [16,17,18]. A general anesthetic widely used in pediatric surgery, was first shown to induce widespread apoptosis in multiple brain regions of neonatal rats [18]. The similarity in the time course of physiological and anesthesia-induced apoptosis suggests potential common regulatory mechanisms. To investigate whether this might be the case, we comprehensively examined the effect of ketamine administration on the pattern of neuronal apoptosis in neonatal mice. Since ketamine mediates its effects primarily by blocking N-Methyl-D-aspartic acid (NMDA) receptors, and the NMDA receptor antagonist MK-801 has been shown to induce apoptosis [18], we investigated the effect of neuronal activity on the ketamine-induced apoptosis using the Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system and environmental enrichment (EE)
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