To further probe the contribution of GIRK-dependent signaling in the hippocampus to fear learning, we assessed the performance of CaMKIICre(+):Girk2 fl/fl mice in trace fear conditioning test. In this paradigm, the trace interval inserted between the presentation of the conditioned (cue/tone) and unconditioned (footshock) stimulus activates temporal memory mechanisms within the hippocampus, thus rendering both contextual and cue fear learning dependent on the hippocampus44, 68. Viral-mediated over-expression of either GIRK2a or GIRK2c in dorsal CA1 pyramidal neurons rescued contextual fear learning in CaMKIICre(+):Girk2 fl/fl mice, suggesting that the fear learning deficit in CaMKIICre(+):Girk2 fl/fl mice is linked to GIRK2 loss in these neurons. Although we did not see a difference in cue fear learning between untreated CaMKIICre(−):Girk2 fl/fl and CaMKIICre(+):Girk2 fl/fl mice, over-expression of GIRK2a, but not GIRK2c, in dorsal CA1 pyramidal neurons significantly enhanced cue learning. The enhanced cue learning seen in CaMKIICre(+):Girk2 fl/fl mice over-expressing GIRK2a in dorsal CA1 pyramidal neurons, together with our evidence that the GIRK2 isoforms contribute in distinct fashion to the processing of inhibitory input to proximal and distal dendritic fields, suggests that trace cue learning may be differentially modulated by inputs from the PP and SC.
