Neurodevelopmental effects of anesthesia and environmental factors

The question of whether early life exposure to general anesthesia induces neurodevelopmental abnormalities in humans, similar to what has been demonstrated in animals from rodents to rhesus monkeys, is complex and of significant clinical concern, given that more than 1 in 4 children undergo procedures requiring anesthesia in their first year of life [1]. Important roadblocks to understanding the developmental outcomes of human exposure to general anesthetics include poor understanding, even in rodents, of the full spectrum of developmental abnormalities, their underlying mechanisms, and their modulation by subsequent life experiences. Rodents become largely resistant to the side effects of general anesthetics by the end of the second postnatal week. The existence of a vulnerable period suggests that prime targets for modulation by general anesthetics are mechanisms unique to this period of life in rodents. One of the unique features of the rodent brain during the first 2 postnatal weeks is relatively high and low expressions of the neuronal Na +-K +-2Cl-Cl-importer and the K +-2Cl-Cl-exporter, respectively. As a result, the transmembrane gradients for Cl-support outward depolarizing Cl-currents through gamma-aminobutyric acid type A receptor (GABA A R) channels. This GABA A R-mediated depolarization is sufficient to activate calcium influxes that play a crucial role in regulation of many developmental processes, including neurogenesis and synaptogenesis. Abnormal GABA A R-mediated depolarization, however, has been linked to a number of developmental disorders, including autism spectrum disorders and schizophrenia. Most general anesthetics enhance GABA A R-mediated currents. Interestingly, the ontogenetic transition in GABA A R-mediated signaling from stimulatory to inhibitory coincides with the age period when rodents become resistant to developmental effects of GABAergic anesthetics. During the first 2 postnatal weeks, rodents undergo a stress hyporesponsive period (SHRP) during which the limbic-hypothalamic-pituitary-adrenal (LHPA) axis — the main stress response system — is hyporesponsive to stressful stimuli. The SHRP is believed to be an important adaptive feature to protect the developing brain from deleterious effects of high levels of stress-related hormones, such as corticosterone. Stressful stimuli that are sufficient to overcome the SHRP, such as prolonged and repeated maternal separations frequently used for this purpose in laboratory settings, lead to neurobehavioral abnormalities and exacerbated endocrine responses to stress in adulthood. The LHPA axis and GABA A R activities are closely linked. For example, neuroactive steroids, released by the adrenal gland in response to stress-induced stimulation of the LHPA axis, down-regulate LHPA axis activity by enhancing GABA …