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The GABA A receptor (GABA A R) mediates most inhibitory neurotransmission. It is widely believed that anesthetics depress neuronal excitability by increasing GABAergic synaptic inhibition. Recently, a tonic inhibitory conductance was identified in several brain regions including the hippocampus. We showed that the tonic but not synaptic conductance in hippocampal pyramidal neurons is generated by α5 subunit-containing GABA A Rs (α5GABA A Rs) (PNAS 101:3662). Here, we examine the effects of subunit-selective modulators and isoflurane on tonic and synaptic currents in pyramidal neurons from wild-type (WT) and α5 subunit null mutant mice (α5−/−). Consistent with α5GABA A Rs generating a tonic current, the α5-selective inverse agonist, L-655,708, reduces the tonic current in WT but not α5−/− neurons while the α5 subunit-sparing imidazopyridine, zolpidem, has similar effects on WT and α5−/− neurons. Low sub-MAC concentrations of isoflurane (≤ 83 μM) increase the tonic conductance in WT but not α5−/− neurons (J Neurosci 29:8454), whereas a high concentration of isoflurane (2500 μM) generates a similar inward current in WT and α5−/− neurons. Since α5GABA A Rs are known to play a role in memory processes, an increase in a tonic conductance in the hippocampus might contribute to the amnestic effects of isoflurane. |
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