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The Journal of Neuroscience, September 29, 2004, 24(39):8454-8458; doi:10.1523/JNEUROSCI.2063-04.2004

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BRIEF COMMUNICATION
Selective Enhancement of Tonic GABAergic Inhibition in Murine Hippocampal Neurons by Low Concentrations of the Volatile Anesthetic Isoflurane

Valerie B. Caraiscos,¹ J. Glen Newell,³ Kong E. You-Ten,² Erin M. Elliott,¹ Thomas W. Rosahl,⁵ Keith A. Wafford,⁵ John F. MacDonald,^3,4 and Beverley A. Orser^1,2,3,6

¹Institute of Medical Science, Departments of ²Anesthesia, ³Physiology, and ⁴Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada, ⁵Merck Sharp and Dohme Research Laboratories, Neuroscience Research Center, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom, and ⁶Department of Anesthesia, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada

Volatile (inhaled) anesthetics cause amnesia at concentrations well below those that cause loss of consciousness and immobility; however, the underlying neuronal mechanisms are unknown. Although many anesthetics increase inhibitory GABAergic synaptic transmission, this effect occurs only at high concentrations (>100 µM). Molecular targets for low concentrations of inhaled anesthetics have not been identified. Here, we report that a tonic inhibitory conductance in hippocampal pyramidal neurons generated by 5 subunit-containing GABA_A receptors is highly sensitive to low concentrations of the volatile anesthetic isoflurane (ISO) (25 and 83.3 µM). The 5 subunit is necessary for enhancement of the tonic current by these low concentrations of isoflurane because potentiation is absent in neurons from 5^-/- mice. Furthermore, ISO (25 µM) potentiated recombinant human 532L GABA_A receptors, whereas this effect was not seen with 132L GABA_A receptors. These studies suggest that an increased tonic inhibition in the hippocampus may contribute to amnestic properties of volatile anesthetics.

Key words: amnesia; anesthesia; GABA; extrasynaptic; 5 subunit; heterologous expression

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Received May 27, 2004; revised August 9, 2004; accepted August 10, 2004.

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