The development of the human brain, including synaptogenesis and dendritic maturation, hinges on a critical period which is thought to begin during the third trimester of pregnancy and end several years into life.1-3 General anesthetics are known to be powerful modulators of neural activity, and their administration during this critical period of brain maturation must be closely monitored.2,4 The prefrontal cortex and how general anesthesia affects its development are of particular interest, given the brain region’s role in higher level cognition.
Synaptogenesis, which is the formation of new synapses – or connections – between neurons, is an essential element of brain growth and development, as well as memory formation. Existing studies demonstrate that general anesthesia affects synaptogenesis in young brains. A 2009 study found that long-term exposure of young rodents to anesthetics rapidly increased synaptic spine density in the hippocampus and somatosensory cortex. General anesthesia was induced via intraperitoneal injection of propofol, midazolam, and ketamine. Compared to non-anesthetized mice, anesthetized animals showed a twofold increase in protrusion density on tufted apical dendrites of layer 5 pyramidal neurons of the somatosensory cortex. This alteration was associated with a significant decrease in mean spine head density of these dendrites. Of the new spines formed after anesthesia induction, only half remained functional; the others did not respond to stimulation by an increase in intracellular calcium. Both propofol and midazolam enhance GABAA receptor-mediated inhibition, while ketamine blocks NMDA receptor-mediated excitation. This finding led the researchers to suggest that synaptogenesis during these critical periods of neural development depends on the balance between excitation and inhibition.5
The same group of researchers conducted a second murine study to investigate the effects of volatile general anesthesia on synaptogenesis, narrowing the ROI to the medial prefrontal cortex (mPFC).2 This region has long been considered one of the most important neural regions for higher-order cognitive and emotional functions, including decision-making, judgment, and perception.6 Rat pups given isoflurane had a gradual, exposure time-dependent increase in both apical and basal dendrites. Sevoflurane induced a more immediate increase in synaptogenesis, doubling both apical and basal dendrite densities after just 30 minutes. By contrast, exposure to desflurane caused a significant increase in dendritic spine density after 2 hours.2 Each of these increases was found to be primarily composed of spines with a smaller head diameter.
In 1989, a pair of researchers from Children’s Hospital in Boston, Massachusetts, published an in vitro study on spine head morphology and synaptic efficacy. Now cited over 1300 times, this seminal study concluded larger spine heads are associated with larger synapses and more vesicles in the presynaptic axonal varicosity. Spine head diameter was also found to directly correlate with the size of the cell’s post-synaptic density, a neuroanatomical indicator of synaptic efficacy.7 These findings gain significance when considering the results of the aforementioned study, which determined general anesthesia-induced increases in synaptic density in the prefrontal cortex were largely due to spines with smaller heads, as these smaller heads may be less effective despite greater numbers.
As far as the extant literature goes, general anesthesia impairs synaptogenesis in the prefrontal cortex during brain development. This is typically through an increase in synaptic spine density but a decrease in spine efficacy. With the prefrontal cortex being such a critical player in human cognitive capabilities, the translational relevance of these studies gains prominence. Previous studies suggest different anesthetics may elicit different effects on synaptogenesis, which is thought to be a result of their molecular binding. Future research should focus on deriving a more conclusive answer.
References
- Cisneros-Franco, J. Miguel, et al. “Critical Periods of Brain Development.” Handbook of Clinical Neurology, vol. 173, 2020, pp. 75–88. PubMed, https://doi.org/10.1016/B978-0-444-64150-2.00009-5
- Briner, Adrian, et al. “Volatile Anesthetics Rapidly Increase Dendritic Spine Density in the Rat Medial Prefrontal Cortex during Synaptogenesis.” Anesthesiology, vol. 112, no. 3, Mar. 2010, pp. 546–56. DOI.org (Crossref), https://doi.org/10.1097/ALN.0b013e3181cd7942
- Briner, Adrian, et al. “Developmental Stage-Dependent Persistent Impact of Propofol Anesthesia on Dendritic Spines in the Rat Medial Prefrontal Cortex.” Anesthesiology, vol. 115, no. 2, Aug. 2011, pp. 282–93. DOI.org (Crossref), https://doi.org/10.1097/ALN.0b013e318221fbbd
- Wilder, Robert T., et al. “Early Exposure to Anesthesia and Learning Disabilities in a Population-Based Birth Cohort.” Anesthesiology, vol. 110, no. 4, Apr. 2009, pp. 796–804. DOI.org (Crossref), https://doi.org/10.1097/01.anes.0000344728.34332.5d
- Roo, Mathias De, et al. “Anesthetics Rapidly Promote Synaptogenesis during a Critical Period of Brain Development.” PLOS ONE, vol. 4, no. 9, Sept. 2009, p. e7043. PLoS Journals, https://doi.org/10.1371/journal.pone.0007043
- Fuster, Joaquin. The Prefrontal Cortex. Academic Press, 2015.
- Harris, K. M., and J. K. Stevens. “Dendritic Spines of CA1 Pyramidal Cells in the Rat Hippocampus: Serial Electron Microscopy with Reference to Their Biophysical Characteristics.” Journal of Neuroscience, vol. 9, no. 8, Aug. 1989, pp. 2982–97. www.jneurosci.org, https://doi.org/10.1523/JNEUROSCI.09-08-02982.1989
