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 brain^1,2.  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)⁵.  Conclusions.  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.

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