Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway

Abstract

Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway

“…Taken together, these data indicate that isoflurane interferes with the formation of excitatory synapses in developing cultured neocortical neurons and that this effect may be due to actions on the mTOR pathway. Our own work in vivo shows that newborn dentate gyrus neurons in mice exposed to GA with isoflurane are found to have reduced numbers of spines overall and profoundly reduced numbers of mushroom morphology spines over a month later [8]. As in our culture model, we found that this effect was reversible by treatment with rapamycin not acutely, but for a week after the exposure.…”

“…Numerous studies have found that early postnatal exposure to GA in rodents results in deficits in performance on tests of learning and memory [7][8][9][10][11][12][13][14][15], but rodent anesthesia models introduce a confound of physiologic perturbation that is hard to measure and also the short timeline of rodent brain development might exaggerate the consequences of a toxic developmental exposure.…”

Astroglial dysfunctions drive aberrant synaptogenesis in developing brain with lengthy general anesthesia

“…Consistent with a previous animal study with propofol (23), we found Sevo lengthy anesthesia induced an increase of dendritic spines and synapses at P21 in the cortex, but decreases were also reported (24, 25). We did not observe significant astrocyte nor neuron structural deficits in developing hippocampal CA1sr and DG-mo regions, whereas a few studies found abnormal synaptic growth (26), altered synaptic plasticity (24) in the hippocampus. The inconsistency may due to different anesthetic agents (isoflurane, sevoflurane, propofol etc.)…”

“…For apical dendrites, the 70 μm long segment was also analyzed every 10 μm of dendritic length. For spine classification, the Filament function of Imaris was used; stubby: length (spine) < 1.5 and max width (head) < mean width (neck) ×1.2; mushroom: max width (head) > mean width (neck) × 1.2 and max width (head) > 0.3; the rest were defined as long-thin (26). We only quantified the total and mushroom spine density, but the stubby and long thin were difficult to be classified in many cases due to the limited image resolution.…”

Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice

“…Additionally, the mTOR pathway was found to take part in the regulation of dendritic growth, synapse formation, and synaptic protein expression [85][86][87]. It was reported that general anesthetics, including sevoflurane, induced developmental neuronal injury by activating the mTOR pathway [87][88][89][90]. In light of the fact that mTOR and BDNF interact in a complicated way in physiological or pathological settings [91,92], we did not explore the crosstalk between BDNF and mTOR signaling in the sevoflurane-induced injury in the present study.…”