Isoflurane Enhances Both Fast and Slow Synaptic Inhibition in the Hippocampus at Amnestic Concentrations

Abstract

Background Inhibition mediated by γ-aminobutyric acid type A (GABA A) receptors has long been considered an important target for a variety of general anesthetics. In the hippocampus, two types of phasic GABA A receptor-mediated inhibition coexist: GABA A,fast, which is expressed primarily at peri-somatic sites, and GABAA,slow, which is expressed primarily in the dendrites. Their spatial segregation suggests distinct functions: GABA A,slow may control plasticity of dendritic synapses, whereas GABA A,fast controls action potential initiation at the soma. We examined modulation of GABA A,fast and GABA A,slow inhibition by isoflurane at amnesic concentrations, and compared it with modulation by behaviorally equivalent doses of the GABA A receptor-selective drug etomidate. Methods Whole cell recordings were obtained from pyramidal cells in organotypic hippocampal cultures prepared from C57BL/6 × 129/SvJ F1 hybrid mice. GABA A receptor-mediated currents were isolated using glutamate receptor antagonists. GABAA,slow currents were evoked by electrical stimulation in the stratum lacunosum-moleculare. Miniature GABA A,fast currents were recorded in the presence of tetrodotoxin. Results 100 μM isoflurane (approximately EC50,amnesia) slowed fast- and slow-inhibitory postsynaptic current decay by approximately 25%. Higher concentrations, up to 400 μM, produced proportionally greater effects without altering current amplitudes. The effects on GABA A,slow were approximately one-half those produced by equi-amnesic concentrations of etomidate. Conclusions Isoflurane enhances both types of phasic GABA A receptor-mediated inhibition to similar degrees at amnesic concentrations. This pattern differs from etomidate, which at low concentrations selectively enhances slow inhibition. These effects of isoflurane are sufficiently large that they may contribute substantially to its suppression of hippocampal learning and memory.