Trace fear conditioning involves hippocampal α₅ GABA_A receptors

The heterogeneity of γ-aminobutyric acid type A (GABA_A) receptors contributes to the diversity of neuronal inhibition in the regulation of information processing. Although most GABA_A receptors are located synaptically, the small population of α₅GABA_A receptors is largely expressed extrasynaptically. To clarify the role of the α₅GABA_A receptors in the control of behavior, a histidine-to-arginine point mutation was introduced in position 105 of the murine α₅ subunit gene, which rendered the α₅GABA_A receptors diazepam-insensitive. Apart from an incomplete muscle relaxing effect, neither the sedative, anticonvulsant, nor anxiolytic-like activity of diazepam was impaired in α₅(H1O5R) mice. However, in hippocampal pyramidal cells, the point mutation resulted in a selective reduction of α₅GABA_A receptors, which altered the drug-independent behavior. In line with the role of the hippocampus in certain forms of associative learning, trace fear conditioning, but not delay conditioning or contextual conditioning, was facilitated in the mutant mice. Trace fear conditioning differs from delay conditioning in that the conditioned and unconditioned stimulus are separated by a time interval. Thus, the largely extrasynaptic α₅GABA_A receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning.