Loss of recall (memory) is an essential component of general anesthesia, yet the mechanisms underlying this important effect remain unknown. Failure to block recall during anesthesia continues to be a health care problem-over 40,000 incidents of recall are reported annually in the United States. Experiments outlined in the proposed research will investigate anesthetic effects on Long Term Potentiation (LTP) of synaptic transmission, as a cellular basis for anesthetic-induced loss of recall. Mechanisms of action leading to a block of LTP will be investigated using electrophysiological recordings and specific pharmacological probes to isolate the synaptic and molecular targets for three widely used agents: isoflurane, propofol and midazolam. Experiments will be conducted using rat hippocampal brain slices and the well characterized Schaffer-collateral fiber to CA 1 pyramidal neuron synaptic circuit-the best studied synapse for LTP in the brain. The hippocampus is essential for learning and memory in humans and animals and LTP is the leading candidate for a cellular basis of learning in hippocampal cortex.
Three Specific Aims will be undertaken in the proposed research: 1) To determine the effective concentration range for anesthetic-induced block of LTP. 2) To determine the involvement of GABA and glutamate-mediated synapses in anesthetic-induced block of LTP. 3) To determine whether postsynaptic actions at or downstream from NMDA receptors contribute to the anesthetic-induced block of LTP. It has not been possible to undertake experiments of this nature before now, because studies of anesthetic concentrations required to block recall, in vivo, have only recently appeared in the literature. Results from our research will provide a quantitative analysis of anesthetic concentrations needed to block LTP, and will determine the mechanisms of action which lead to this block. An understanding of the mechanisms of anesthetic-induced block of LTP could lead to the development of highly targeted agents for producing loss of recall during anesthesia-this could minimize undesirable side effects produced by anesthetics in current use. Preliminary results from our laboratory indicate that isoflurane blocks LTP at concentrations which are indistinguishable from those that block recall in humans, and considerably lower than those needed to block synaptic transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054767-08
Application #
6744740
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1997-05-01
Project End
2005-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
8
Fiscal Year
2004
Total Cost
$317,678
Indirect Cost
Name
Stanford University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Bieda, Mark C; Su, Henry; Maciver, M Bruce (2009) Anesthetics discriminate between tonic and phasic gamma-aminobutyric acid receptors on hippocampal CA1 neurons. Anesth Analg 108:484-90
Sceniak, Michael P; Maciver, M Bruce (2008) Slow GABA(A) mediated synaptic transmission in rat visual cortex. BMC Neurosci 9:8
Winegar, Bruce D; MacIver, M Bruce (2006) Isoflurane depresses hippocampal CA1 glutamate nerve terminals without inhibiting fiber volleys. BMC Neurosci 7:5
Lukatch, Heath S; Kiddoo, Cynthia E; Maciver, M Bruce (2005) Anesthetic-induced burst suppression EEG activity requires glutamate-mediated excitatory synaptic transmission. Cereb Cortex 15:1322-31
Bieda, Mark C; MacIver, M Bruce (2004) Major role for tonic GABAA conductances in anesthetic suppression of intrinsic neuronal excitability. J Neurophysiol 92:1658-67
Gredell, J A; Turnquist, P A; Maciver, M B et al. (2004) Determination of diffusion and partition coefficients of propofol in rat brain tissue: implications for studies of drug action in vitro. Br J Anaesth 93:810-7
Pittson, Sky; Himmel, Allison M; MacIver, M Bruce (2004) Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices. BMC Neurosci 5:52
Lingamaneni, R; Krasowski, M D; Jenkins, A et al. (2001) Anesthetic properties of 4-iodopropofol: implications for mechanisms of anesthesia. Anesthesiology 94:1050-7
Nishikawa, K; MacIver, M B (2001) Agent-selective effects of volatile anesthetics on GABAA receptor-mediated synaptic inhibition in hippocampal interneurons. Anesthesiology 94:340-7
Nishikawa, K; MacIver, M B (2000) Excitatory synaptic transmission mediated by NMDA receptors is more sensitive to isoflurane than are non-NMDA receptor-mediated responses. Anesthesiology 92:228-36

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