Human and animal studies have elucidated the apparent neurodevelopmental effects resulting from neonatal anesthesia. Observations of learning and behavioral deficits in children, who were exposed to anesthesia early in development, have instigated a flurry of studies that have predominantly utilized animal models to further interrogate the mechanisms of neonatal anesthesia-induced neurotoxicity. Specifically, while neonatal anesthesia has demonstrated its propensity to affect multiple cell types in the brain, it has shown to have a particularly detrimental effect on the gamma aminobutyric acid (GABA)ergic system, which contributes to the observed learning and behavioral deficits. The damage to GABAergic neurons, resulting from neonatal anesthesia, seems to involve structure-specific changes in excitatory-inhibitory balance and neurovascular coupling, which manifest following a significant interval after neonatal anesthesia exposure. Thus, to better understand how neonatal anesthesia affects the GABAergic system, we first review the early development of the GABAergic system in various structures that have been the focus of neonatal anesthesia research. This is followed by an explanation that, due to the prolonged developmental curve of the GABAergic system, the entirety of the negative effects of neonatal anesthesia on learning and behavior in children are not immediately evident, but instead take a substantial amount of time (years) to fully develop. In order to address these concerns going forward, we subsequently offer a variety of in vivo methods which can be used to record these delayed effects.

Neonatal anesthesia, while often essential for surgeries or imaging procedures, is accompanied by significant risks to redox balance in the brain due to the relatively weak antioxidant system in children. Oxidative stress is characterized by concentrations of reactive oxygen species (ROS) that are elevated beyond what can be accommodated by the antioxidant defense system. In neonatal anesthesia, this has been proposed to be a contributing factor to some of the negative consequences (e.g., learning deficits and behavioral abnormalities) that are associated with early anesthetic exposure. In order to assess the relationship between neonatal anesthesia and oxidative stress, we first review the mechanisms of action of common anesthetic agents, the key pathways that produce the majority of ROS, and the main antioxidants. We then explore the possible immediate, short-term, and long-term pathways of neonatal-anesthesia-induced oxidative stress. We review a large body of literature describing oxidative stress to be evident during and immediately following neonatal anesthesia. Moreover, our review suggests that the short-term pathway has a temporally limited effect on oxidative stress, while the long-term pathway can manifest years later due to the altered development of neurons and neurovascular interactions.

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The functional deficiency of the inhibitory system typically appears during development and can progress to psychiatric disorders or epilepsy, depending on its severity, in later years. It is known that interneurons, the major source of GABAergic inhibition in the cerebral cortex, can make direct connections with arterioles and participate in the regulation of vasomotion. The goal of this study was to mimic the functional deficiency of interneurons through the use of localized microinjections of the GABA antagonist, picrotoxin, in such a concentration that it did not elicit epileptiform neuronal activity. First, we recorded the dynamics of resting-state neuronal activity in response to picrotoxin injections in the somatosensory cortex of an awake rabbit; second, we assessed the altered neuronal and hemodynamic responses to whisker stimulation using BOLD fMRI and electrophysiology recordings; third, we evaluated brain tissue oxygen levels before and after picrotoxin injection. Our results showed that neuronal activity typically increased after picrotoxin administration, the BOLD responses to stimulation became negative, and the oxygen response was nearly abolished. Vasoconstriction during the resting baseline was not observed. These results indicate that picrotoxin provoked imbalanced hemodynamics either due to increased neuronal activity, decreased vascular response, or a combination of both.

The dynamic interaction between excitatory and inhibitory activity in the brain is known as excitatory-inhibitory balance (EIB). A significant shift in EIB toward excitation has been observed in numerous pathological states and diseases, such as autism or epilepsy, where interneurons may be dysfunctional. The consequences of this on neurovascular interactions remains to be elucidated. Specifically, it is not known if there is an elevated metabolic consumption of oxygen due to increased excitatory activity. To investigate this, we administered microinjections of picrotoxin, a gamma aminobutyric acid (GABA) antagonist, to the rabbit cortex in the awake state to mimic the functional deficiency of GABAergic interneurons. This caused an observable shift in EIB toward excitation without the induction of seizures. We used chronically implanted electrodes to measure both neuronal activity and brain tissue oxygen concentrations (PO2) simultaneously and in the same location. Using a high-frequency recording rate for PO2, we were able to detect two important phenomena, (1) the shift in EIB led to a change in the power spectra of PO2 fluctuations, such that higher frequencies (8–15 cycles per minute) were suppressed and (2) there were brief periods (dips with a duration of less than 100 ms associated with neuronal bursts) when PO2 dropped below 10 mmHg, which we defined as the threshold for hypoxia. The dips were followed by an overshoot, which indicates either a rapid vascular response or decrease in oxygen consumption. Our results point to the essential role of interneurons in brain tissue oxygen regulation in the resting state.