Anesthetic sensitivity is reduced in hippocampal pyramidal neurons from GABAA receptor α5 subunit null mutant mice

The GABAA receptor (GABAAR) 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 GABAARs (α5GABAARs) (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 α5GABAARs 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 α5GABAARs 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.