Trace and contextual fear conditioning is enhanced in mice lacking the α4 subunit of the GABAA receptor

The GABA A R α4 subunit is highly expressed in the dentate gyrus region of the hippocampus at predominantly extra-synaptic locations where, along with the GABA A R δ subunit, it forms GABA A receptors that mediate a tonic inhibitory current. The present study was designed to test hippocampus-dependent and hippocampus-independent learning and memory in GABA A R α4 subunit-deficient mice using trace and delay fear conditioning, respectively. Mice were of a mixed C57Bl/6J X 129S1/X1 genetic background from α4 heterozygous breeding pairs. The α4-knockout mice showed enhanced trace and contextual fear conditioning consistent with an enhancement of hippocampus-dependent learning and memory. These enhancements were sex-dependent, similar to previous studies in GABA A R δ knockout mice, but differences were present in both males and females. The convergent findings between α4 and δ-knockout mice suggests that tonic inhibition mediated by α4βδ GABA A receptors negatively modulates learning and memory processes and provides further evidence that tonic inhibition makes important functional contributions to learning and behavior.