Major Role For Tonic GABA_A Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Abstract

Bieda, Mark C. and M. Bruce MacIver. Major role for tonic GABA A conductances in anesthetic suppression of intrinsic neuronal excitability. J Neurophysiol 92: 1658 -1667, 2004. First published May 12, 2004 10.1152/jn.00223.2004. Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABA A inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABA A but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABA A -mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABA A -mediated inhibition using the GABA A receptor antagonist SR95531 (gabazine). Gabazine (20 M) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABA A inhibition. Glutamatergic synaptic responses were not altered by propofol (Յ30 M). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABA A conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABA A conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

“…Latency of ST-EPSCs was unaffected by 30 µM propofol. In contrast, in cortical neurons, sodium channels, spiking and nerve conduction are inhibited by low micromolar propofol concentrations (Rehberg & Duch, 1999;Bieda & MacIver, 2004;Martella et al, 2005;Jones et al, 2007). We conclude that the afferent axon and terminal excitation process is remarkably insensitive to propofol and this may reflect the expression of a particular complement of ion channels within peripheral afferent neuron axons (Schild et al, 1994;Schild & Kunze, 1995).…”

“…Thus, on average, the mean amplitude of the first evoked ST-EPSC (ST-EPSC 1 ) remained unchanged from control up to the highest concentration tested propofol (30 µM, Figure 5B). Although in cortical neurons sodium channels, spiking and nerve conduction are inhibited by low micromolar propofol concentrations (Rehberg & Duch, 1999;Bieda & MacIver, 2004;Martella et al, 2005;Jones et al, 2007), ST-EPSC latency remained constant during propofol (p=0.958, n=5, Figure 5C), a finding that suggests that sensory axon conduction and glutamate release are unimpeded by the anesthetic. Likewise, following pharmacological isolation of sEPSCs with gabazine, propofol did not alter decay-time constants, amplitudes, frequencies or the holding current at any concentration tested (n=6, Figure 5D).…”

“…In cases in which phasic currents were blocked, 30 seconds of the digitized current traces was plotted as an all-points histogram (e.g. (Bieda & MacIver, 2004)) in 0.5 pA bins and all values were then averaged to represent the mean current for that time period. The all-points histograms express variation in current during the time period.…”

“…Increasing interest has focused on propofol actions to induce an inhibitory tonic current that is pharmacologically and biophysically separable from phasic GABAergic currents (Hales & Lambert, 1991;Bai et al, 2001;Yeung et al, 2003). In hippocampal neurons, this tonic, "extrasynaptic" GABA A component is more sensitive to anesthetics than actions on phasic currents in the same neurons (Hemmings, Jr. et al, 2005) and seemingly plays a substantial role in suppressing neuronal excitability (Bieda & MacIver, 2004). In addition, ion channels and in particular voltage-gated sodium channels are reported to be inhibited by low micromolar concentrations of propofol (Frenkel & Urban, 1991;Ouyang et al, 2003;Jones et al, 2007).…”

The GABAA agonist muscimol attenuates induced airway constriction in guinea pigs in vivo

“…Activation of GABA A channels in mature central nervous system neurons results in an inward chloride flux resulting in hyperpolarization of the cell membrane (2). In airway smooth muscle, plasma membrane hyperpolarization favors relaxation (11).…”