Abstract
SummaryVolatile anesthetics induce hyperactivity during induction while producing anesthesia at higher concentrations. They also bidirectionally modulate many neuronal functions. However, the neuronal mechanism is unclear. The effects of isoflurane on sodium channel currents were analyzed in acute mouse brain slices, including sodium leak (NALCN) currents and voltage-gated sodium channels (Nav) currents. Isoflurane at sub-anesthetic concentrations increased the spontaneous firing rate of CA3 pyramidal neurons, whereas anesthetic concentrations of isoflurane decreased the firing rate. Isoflurane at sub-anesthetic concentrations enhanced NALCN conductance but minimally inhibited Nav currents. Isoflurane at anesthetic concentrations depressed Nav currents and action potential amplitudes. Isoflurane at sub-anesthetic concentrations depolarized resting membrane potential (RMP) of neurons, whereas hyperpolarized the RMP at anesthetic concentrations. Isoflurane at low concentrations induced hyperactivity in vivo, which was diminished in NALCN knockdown mice. In conclusion, enhancement of NALCN by isoflurane contributes to its bidirectional modulation of neuronal excitability and the hyperactivity during induction.
Highlights
IntroductionGeneral anesthetics disrupt the balance of inhibitory and excitatory neurotransmission to produce widespread depression in the central nervous system (Becker et al, 2012; Clark and Rosner, 1973; Leung et al, 2014; Palanca et al, 2017; Son, 2010)
Enhancement of NALCN by isoflurane contributes to its bidirectional modulation of neuronal excitability and the hyperactivity during induction
General anesthetics disrupt the balance of inhibitory and excitatory neurotransmission to produce widespread depression in the central nervous system (Becker et al, 2012; Clark and Rosner, 1973; Leung et al, 2014; Palanca et al, 2017; Son, 2010)
Summary
General anesthetics disrupt the balance of inhibitory and excitatory neurotransmission to produce widespread depression in the central nervous system (Becker et al, 2012; Clark and Rosner, 1973; Leung et al, 2014; Palanca et al, 2017; Son, 2010). Isoflurane increased hippocampal CA1 neuronal excitability at sub-anesthetic concentration and produced postsynaptic depression of dentate neurons at anesthetic concentrations (MacIver and Roth, 1988). Specific volatile anesthetics such as enflurane can even induce seizures (Sleigh et al, 2009; Voss et al, 2008). Diverse neuronal functions, including synaptic transmission and plasticity, have been found to be bidirectionally modulated by volatile anesthetics (MacIver, 2014; Ogawa et al, 2011; Otsubo et al, 2008; Xiao et al, 2016) It is unclear how volatile anesthetics exert bidirectional modulation of neuronal excitability. Stabilized maintenance and recovery can improve quality of general anesthesia and safety of patients throughout
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