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

The GABAAR α4 subunit is highly expressed in the dentate gyrus region of the hippocampus at predominantly extra synaptic locations where, along with the GABAAR δ subunit, it forms GABAA receptors that mediate a tonic inhibitory current. The present study was designed to test hippocampus-dependent and hippocampus-independent learning and memory in GABAAR 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 GABAAR 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 GABAA receptors negatively modulates learning and memory processes and provides further evidence that tonic inhibition makes important functional contributions to learning and behavior.