Anesthetics Rapidly Promote Synaptogenesis during a Critical Period of Brain Development

Abstract

Experience-driven activity plays an essential role in the development of brain circuitry during critical periods of early postnatal life, a process that depends upon a dynamic balance between excitatory and inhibitory signals. Since general anesthetics are powerful pharmacological modulators of neuronal activity, an important question is whether and how these drugs can affect the development of synaptic networks. To address this issue, we examined here the impact of anesthetics on synapse growth and dynamics. We show that exposure of young rodents to anesthetics that either enhance GABAergic inhibition or block NMDA receptors rapidly induce a significant increase in dendritic spine density in the somatosensory cortex and hippocampus. This effect is developmentally regulated; it is transient but lasts for several days and is also reproduced by selective antagonists of excitatory receptors. Analyses of spine dynamics in hippocampal slice cultures reveals that this effect is mediated through an increased rate of protrusions formation, a better stabilization of newly formed spines, and leads to the formation of functional synapses. Altogether, these findings point to anesthesia as an important modulator of spine dynamics in the developing brain and suggest the existence of a homeostatic process regulating spine formation as a function of neural activity. Importantly, they also raise concern about the potential impact of these drugs on human practice, when applied during critical periods of development in infants.

Propofol Anesthesia Impairs the Maturation and Survival of Adult-born Hippocampal Neurons

“…21,37,38 This discrepancy suggests that the effect of propofol on dendritic spine density is specific to postnatal development and supports the view that it may be mediated by network activity rather than being entirely cell autonomous. It is, nevertheless, important to note that the propofol-induced reduction in dendritic length on adult-born neurons, as observed in the current study, reduces the overall axospinous innervation on new neurons.…”

Structural plasticity upon learning: regulation and functions

“…Although it remains unclear how exactly modulation of the excitatory-inhibitory balance can promote or reduce cortical plasticity, part of the effect could implicate changes in synapse dynamics. Consistent with this possibility, spine changes correlate with the capacity for visual plasticity in vivo 44 and, during development, short-term anaesthesia or administration of drugs that enhance GABAergic inhibition results in rapid and marked changes in spine growth and synapse gain 45 .…”

The dialectic of Hebb and homeostasis

“…There is little definitive evidence in support of this idea. Both LTP [46] and synaptic scaling [11] are correlated with changes in spine size, suggesting that both affect PSD area. On the other hand, although prolonged activity blockade (3-6 days) is able to expand the size of the PSD [47], this happens on a much slower timescale than the rapid increases in receptor accumulation that can be observed in vitro within an hour of activity blockade [15].…”