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Vol. 63, Issue 1, 2-8, January 2003
Institute of Medical Science (J.Y.T.Y., B.A.O.) and Departments of
Anesthesia (K.J.C., B.A.O.), Physiology (G.Z., J.F.M, B.A.O.), and
Pharmaceutical Sciences (P.P, J.F.M.), University of Toronto, Toronto,
Ontario, Canada; and Department of Anesthesia, Sunnybrook and Women's
College Health Science Center, Toronto, Ontario, Canada (B.A.O.)
In the hippocampus, two distinct forms of GABAergic inhibition
have been identified, phasic inhibitory postsynaptic currents that are
the consequence of the vesicular release of GABA and a tonic
conductance that is activated by low ambient concentrations of
extracellular GABA. It is not known what accounts for the distinct properties of receptors that mediate the phasic and tonic inhibitory conductances. Moreover, the physiological role of the tonic inhibitory conductance remains uncertain because pharmacological tools that clearly distinguish tonic and phasic receptors are lacking. Here, we
demonstrate that GABAA receptors that generate a tonic
conductance in cultured hippocampal neurons from embryonic mice have
different pharmacological properties than those in cerebellar granule
neurons or pyramidal neurons in the dentate gyrus. The tonic
conductance in cultured hippocampal neurons is enhanced by the
benzodiazepine, midazolam, and is insensitive to the inhibitory effects
of the competitive antagonist, gabazine (
10 µM). We also identify
penicillin as an uncompetitive antagonist that selectively inhibits the
synaptic but not tonic conductance. GABA was applied to hippocampal
neurons to investigate the properties of synaptic and extrasynaptic
receptors. GABA-evoked current was composed of two components: a
rapidly desensitizing current that was blocked by penicillin and a
nondesensitizing current that was insensitive to penicillin blockade.
The potency of GABA was greater for the penicillin-insensitive
nondesensitizing current. Single-channel studies show that the
gabazine-insensitive GABAA receptors have a lower unitary
conductance (12 pS) than that estimated for synaptic receptors. Thus,
specialized GABAA receptors with an apparent higher
affinity for GABA that do not readily desensitize mediate the
persistent tonic conductance in hippocampal neurons. The receptors
underlying tonic and phasic inhibitory conductances in hippocampal
neurons are pharmacologically and biophysically distinct, suggesting
that they serve different physiological roles.
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