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Isoflurane-Induced Depression of Synaptic LTP Does Not Involve Post-NMDA Receptor Mediated Mechanisms
Kenny H.-T. Cheung; M. Bruce MacIver, M.Sc., Ph.D.
Anesthesia, Stanford Medical School, Palo Alto, California
Introduction: Several previous studies have suggested that anesthetic-induced block of recall might result, at least in part, from a depression of hippocampal synapse Long Term Potentiation (LTP). This is based on the observations that isoflurane blocks LTP (1,2) at concentrations that are close to those needed to block recall and learning in humans and animals (3,4). The present study determined whether isoflurane-induced depression of LTP involved sites of action down stream from synaptic sites of action.

Methods: Synaptic responses were measured using electrophysiological recording from rat hippocampal brain slices. A stimulating electrode was placed in stratum radiatum to activate Schaffer-collateral fiber inputs to CA 1 neurons. An extracellular field electrode was placed in the dendritic regions of these neurons to record excitatory postsynaptic potentials (EPSPs). The EPSP responses where tested at 20 s intervals throughout each experiment. LTP was induced using a 1 s train of 100 stimuli (tetanic) to generate NMDA synapse dependent LTP, or by a 5 min application of 4-aminopyridine (4AP; 10 mM) to bypass NMDA receptors and produce a direct depolarization of the CA 1 neurons. Isoflurane was applied in the perfusate after being bubbled with the carrier gas (O2/CO2, 95/5 %) into the artificial cerebrospinal fluid, which continuously perfused the brain slices (1 ml/min).

Results: In agreement with previous findings from a number of labs, tetanic stimulation produced a form of LTP which was blocked by the NMDA receptor antagonist APV. This form of LTP was also blocked by concentrations of isoflurane, which have been shown to block recall in rats and humans (0.5 vol %; less than half MAC for rats). 4AP also produced LTP, in agreement with previous studies, but this form of LTP was not blocked by the NMDA receptor antagonist – indicating that this form of LTP did not require calcium entry through these receptors. The 4AP-induced LTP was not blocked by isoflurane at concentrations up to 1.0 vol % -- well above those needed to block tetanic LTP and learning.

Discussion: These results support the idea that LTP is related to learning and memory, as well as previous studies suggesting that isoflurane-induced depression of LTP could contribute to the anesthetic-induced block of recall. Also in agreement with earlier studies, the results suggest that isoflurane blocks LTP at CA 1 neuron synapses by actions at synaptic sites. Once calcium entry into CA 1 neurons occurs, subsequent stages of LTP induction were not depressed by isoflurane.

References: 1) MacIver MB et al Br J Anaesth 1989 62(3):301-10; 2) Simon W et al Anesthesiology 2001 94(6):1058-65; 3) Anderson RJ et al ASA Abstract 2001; 4) Dutton RC Anesthesiology 2001 94(3):514-9

Anesthesiology 2002; 96: A815