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

The GABA(A)R alpha 4 subunit is highly expressed in the dentate gyrus region of the hippocampus at predominantly extra synaptic locations where, along with the GABA(A)R delta 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 alpha 4 subunit-deficient mice using trace and delay fear conditioning, respectively. Mice were of a mixed C57B1/6J X 129S1/X1 genetic background from alpha 4 heterozygous breeding pairs. The alpha 4-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 delta knockout mice, but differences were present in both males and females. The convergent findings between alpha 4 and S knockout mice suggests that tonic inhibition mediated by alpha 4 beta delta GABA(A) receptors negatively modulates learning and memory processes and provides further evidence that tonic inhibition makes important functional contributions to learning and behavior. Published by Elsevier Inc.