We utilized a trace fear conditioning protocol to assess the impact of viral treatment on fear learning behavior, as both contextual and cue fear learning in this model are supported by the dorsal hippocampus44, 45. Untreated CaMKIICre(+):Girk2 fl/fl mice, as well as CaMKIICre(+):Girk2 fl/fl mice treated with control virus, exhibited a deficit in contextual fear learning in this model (Fig. 7D), consistent with the contribution of GIRK-dependent signaling in dorsal CA1 to this behavior. Over-expression of either GIRK2a or GIRK2c in dorsal CA1 pyramidal neurons restored contextual fear learning in CaMKIICre(+):Girk2 fl/fl mice (Fig. 7D). Interestingly, while untreated CaMKIICre(+):Girk2 fl/fl mice, and CaMKIICre(+):Girk2 fl/fl mice treated with control virus, exhibited normal cue fear learning, over-expression of GIRK2a but not GIRK2c in dorsal CA1 pyramidal neurons from CaMKIICre(+):Girk2 fl/fl mice significantly enhanced cue fear learning (Fig. 7E). Thus, GIRK2a and GIRK2c exert overlapping but distinct influences on dissociable forms of hippocampal-dependent fear learning.
