Abstract
The brain functions can be reversibly modulated by the action of general anesthetics. Despite a wide number of pharmacological studies, an extensive analysis of the cellular determinants of anesthesia at the microcircuits level is still missing. Here, by combining patch-clamp recordings and mathematical modeling, we examined the impact of sevoflurane, a general anesthetic widely employed in the clinical practice, on neuronal communication. The cerebellar microcircuit was used as a benchmark to analyze the action mechanisms of sevoflurane while a biologically realistic mathematical model was employed to explore at fine grain the molecular targets of anesthetic analyzing its impact on neuronal activity. The sevoflurane altered neurotransmission by strongly increasing GABAergic inhibition while decreasing glutamatergic NMDA activity. These changes caused a notable reduction of spike discharge in cerebellar granule cells (GrCs) following repetitive activation by excitatory mossy fibers (mfs). Unexpectedly, sevoflurane altered GrCs intrinsic excitability promoting action potential generation. Computational modelling revealed that this effect was triggered by an acceleration of persistent sodium current kinetics and by an increase in voltage dependent potassium current conductance. The overall effect was a reduced variability of GrCs responses elicited by mfs supporting the idea that sevoflurane shapes neuronal communication without silencing neural circuits.
Highlights
The brain functions can be reversibly modulated by the action of general anesthetics
We have employed the cerebellar micro-circuitry as an experimental model of the information processing in the CNS to investigate the impact of sevoflurane on neurotransmission
The application of sevoflurane did not significantly affect Excitatory Post-Synaptic Currents (EPSCs) peak amplitudes (1st peak change + 3.5 ± 1.8%, p > 0.35; n = 5, Fig. 1B). This result is in accordance with our recent findings on desflurane, a chemical compound of the same family of sevoflurane, showing that glutamate AMPA receptors are not targeted by the anesthetic[33]
Summary
The brain functions can be reversibly modulated by the action of general anesthetics. As a side effect of their action, these anesthetics impair synaptic long-term potentiation hampering neuronal ability to store information[9] In epileptic patients these drugs increase seizure a ctivity[10] and induce delirium and agitation during the recovery phases[11]. The anesthesia could act by reducing the number of discriminable functional states in an integrated system as well as the complexity of the overall neural s tate[13] These findings represent the state of the art in the knowledge of the effects of anesthetics at integrative level, a more detailed analysis of the changes in neuronal communication induced by anesthetics is still required. Understanding the cellular mechanisms through which the cerebellum is modulated by general anesthetics could help understanding the mechanisms of induction and recovery from anesthesia
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