Deleterious Effects of General Anesthetic Agents on the Developing Brain via Actions on the mTOR Signaling Pathway

Brian Scot Welborn II

Introduction.  Neuronal synaptogenesis is the most sensitive neurodevelopment period.  It begins around 20 weeks of gestation and continues throughout adolescence.  Repeated or long-term exposure to general anesthetic agents may have a significant impact on synaptogenesis and neuroapoptosis in the developing brain1,2.  The neurotoxic effects of general anesthetic agents on the developing brain is well-documented in various animal models, but the impact and underlying mechanisms remain unclear in humans2.  The mechanistic target of rapamycin (mTOR) is normally involved in cell proliferation and survival; however, upregulation of mTOR appears to be a common mechanism for the deleterious impact on synaptogenesis observed with many commonly used general anesthetic agents during the neurodevelopmental period.  Methods.  Downstream markers indicating mTOR pathway activation and excitatory pre/post-synaptic elements were quantified with fluorescent immunocytochemistry.  Dentate gyrus neuron functioning and spatial learning in the rodent model were analyzed through object-place recognition and Y-maze tests.  Emotional dysregulation in the nonhuman primate model was assessed with the Human Intruder task.  Results.  6 hours of 1.8% isoflurane treatment caused a significant increase in the percentage of pS6 positive neurons compared to the control group (64.25 +/- 15.95% vs. 17.22 +/- 10.15%, p < 0.0001), and it resulted in a significant decrease in the intensity of Synapsin-1 immunoreactivity compared to the control (20.46 +/- 7.33% vs. 48.95 +/- 19.02%, p < 0.001) and Homer-1 immunoreactivity compared to the control (30.47 +/- 5.22% vs. 68.46 +/- 11.18%, p < 0.0001) in cultured neocortical neurons3.  Neurons in the isoflurane-exposed rodent model exhibited an 83% increase in total dendritic arbor length (p < 0.005), and the Sholl analysis revealed a significant increase in dendrite arbor complexity with isoflurane exposure (p < 0.0001)4.  The rodent model exhibited a significant reduction in performance during the spatial learning tasks (object-place recognition test, p < 0.05; Y-maze test, p < 0.01)4.  Sevoflurane anesthesia infants in the nonhuman primate model expressed significantly more anxious behaviors overall as compared to controls (anesthesia 11.04 +/- 1.68, control 4.79 +/- 0.77, p = 0.016)5Conclusions.  Isoflurane disrupts the formation of pre-synaptic (Synapsin-1) and post-synaptic (Homer-1) elements of excitatory synapses during developmental periods in cultured neocortical neurons via upregulation of the mTOR pathway3.  Upregulation of the mTOR pathway leads to dendrite growth acceleration/overgrowth which impacts the function of the neuronal synaptic field4.  This results in substantial loss of synaptic connections and impairment of spatial learning in the rodent model4.  In the nonhuman primate model, increased anxiety behaviors persisted for 5 months implicating the long-term effects due to anesthetic exposure5.

 

  1. Andropoulos DB. Effect of anesthesia on the developing Brain: Infant and fetus. Fetal Diagnosis and Therapy. 2018;43(1):1-11. doi:10.1159/000475928.
  2. Bartels DD, McCann ME, Davidson AJ, Polaner DM, Whitlock EL, Bateman BT. Estimating pediatric general anesthesia exposure: Quantifying duration and risk. Pediatric Anesthesia. 2018;28(6):520-527. doi:10.1111/pan.13391.
  3. Xu J, Mathena RP, Xu M, et al. Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway. International Journal of Molecular Sciences. 2018;19(8):2183. doi:10.3390/ijms19082183.
  4. Liu F-F, Zhao S, Liu P, Huo S-P. Influence of mTOR signaling pathway on ketamine-induced injuries in the hippocampal neurons of rats. Neurological Research. 2019;41(1):77-86. doi:10.1080/01616412.2018.1531203.
  5. Raper J, Alvarado MC, Murphy KL, Baxter MG. Multiple Anesthetic Exposure in Infant Monkeys Alters Emotional Reactivity to an Acute Stressor. Anesthesiology. 2015;123(5):1084-1092. doi:10.1097/ALN.0000000000000851.