Isoflurane Modulates Hippocampal Cornu Ammonis Pyramidal Neuron Excitability by Inhibition of Both Transient and Persistent Sodium Currents in Mice

Abstract

Background: Volatile anesthetics inhibit presynaptic voltage-gated sodium channels to reduce neurotransmitter release, but their effects on excitatory neuron excitability by sodium current inhibition are unclear. The authors hypothesized that inhibition of transient and persistent neuronal sodium currents by the volatile anesthetic isoflurane contributes to reduced hippocampal pyramidal neuron excitability. Methods: Whole-cell patch-clamp recordings of sodium currents of hippocampal cornu ammonis pyramidal neurons were performed in acute mouse brain slices. The actions of isoflurane on both transient and persistent sodium currents were analyzed at clinically relevant concentrations of isoflurane. results: The median inhibitory concentration of isoflurane for inhibition of transient sodium currents was 1.0 ± 0.3 mM (~3.7 minimum alveolar concentration [MAC]) from a physiologic holding potential of −70 mV. Currents from a hyperpolarized holding potential of −120 mV were minimally inhibited (median inhibitory concentration = 3.6 ± 0.7 mM, ~13.3 MAC). Isoflurane (0.55 mM; ~2 MAC) shifted the voltage-dependence of steady-state inactivation by −6.5 ± 1.0 mV (n = 11, P < 0.0001), but did not affect the voltage-dependence of activation. Isoflurane increased the time constant for sodium channel recovery from 7.5 ± 0.6 to 12.7 ± 1.3 ms (n = 13, P < 0.001). Isoflurane also reduced persistent sodium current density (median inhibitory concentration = 0.4 ± 0.1 mM, ~1.5 MAC) and resurgent currents. Isoflurane (0.55 mM; ~2 MAC) reduced action potential amplitude, and hyperpolarized resting membrane potential from −54.6 ± 2.3 to −58.7 ± 2.1 mV (n = 16, P = 0.001). conclusions: Isoflurane at clinically relevant concentrations inhibits both transient and persistent sodium currents in hippocampal cornu ammonis pyramidal neurons. These mechanisms may contribute to reductions in both hippocampal neuron excitability and synaptic neurotransmission.

HDAC2 hyperexpression alters hippocampal neuronal transcription and microglial activity in neuroinflammation-induced cognitive dysfunction

“…Accumulating evidence suggests that neuroinflammation and anaesthetics play critical roles in cognitive impairment [65–67]. However, the divergence in results from various studies demonstrates that the underlying mechanism needs to be further investigated [68–70]. In the present study, LPS-impaired object recognition and fear learning were not aggravated by ISO in adult mice, which suggested that a single use of ISO would not increase memory deficits in young patients with acute abdominal inflammation.…”

The General Anesthetic Isoflurane Bilaterally Modulates Neuronal Excitability

“…Sodium channels are important for determining the neuronal excitability and action potential (AP) discharge in the CNS (Eijkelkamp et al, 2012;Wang et al, 2017). Volatile anesthetics at clinically relevant concentrations inhibit voltage-gated sodium channel (Na v ) currents in transfected cells (Herold et al, 2009;Yamada-Hanff and Bean, 2015;Zhou et al, 2019), nerve terminals (Ouyang et al, 2003;Yamada-Hanff and Bean, 2015), dorsal root ganglia (DRG) (Scholz et al, 1998;Zhou et al, 2011), and hippocampal neurons (Zhao et al, 2019). Isoflurane reduces AP amplitude and frequency (Wu et al, 2004;Zhao et al, 2019), which may also be mediated by inhibition of sodium channels.…”

Neuronal excitability and sensory responsiveness in the thalamo‐cortical network in a novel rat model of isoelectric brain state

“…An analogous decrease in membrane excitability was observed in cortical, hippocampal and thalamic neurons in vivo during a barbiturate-induced isoelectric brain state (Altwegg-Boussac et al 2014, 2016, as well as in cortical neurons and motoneurons experiencing elevated doses of isoflurane in vitro (Berg-Johnsen & Langmoen, 1987, 1990El-Beheiry & Puil, 1989b;Sirois et al 1998). This reduced cell excitability could result from the V m hyperpolarization (Shu et al 2003;Altwegg-Boussac et al 2014) and/or from the inhibitory action of isoflurane on sub-threshold sodium currents (Sirois et al 1998;Zhao et al 2019). Augmented values of threshold current were accompanied by a robust enhancement (by ∼45%) of the neuronal gain, contrasting with the attenuation or stability of F-I curve slopes in the barbiturate model (Altwegg-Boussac et al 2014).…”