Pharmacological demonstration of the differential involvement of protein kinase C isoforms in short- and long-term memory formation and retrieval of one-trial avoidance in rats

Rationale: The hippocampal protein kinase C (PKC) family is involved in the early events of consolidation of long-term potentiation (LTP) and long-term memory (LTM). Results so far are indecisive about which PKC isoform is involved and as to whether any of them plays a role in short-term memory (STM) processes, which have recently been shown to be separate from those of LTM in the hippocampus-dependent one-trial step-down inhibitory avoidance task. Objectives: To measure the effect of two PKC inhibitors, one (Gb 6976) selective to the calcium-dependent isoforms a and PI, and the other (Gb 7874) unspecific as to PKC isoforms on the formation and retrieval of STM and LTM of one-trial inhibitory avoidance. Methods: Rats bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus were trained in one-trial step-down inhibitory avoidance. The effect of these two drugs on STM and LTM formation was investigated as follows. Animals were infused 10 min before or 50, 110, or 170 min after inhibitory avoidance training with a vehicle (2% dimethylsulfoxide in saline), or with Go 6976 (0.92 nM or 4.6 nM) or Gb 7874 (1.96 nM or 8 nM) dissolved in the vehicle. Infusion volume was 0.5 mu l in all cases. Animals were tested 1.5 h and 3 h after training for STM and at 24 h for LTM. In order to study the effects of these compounds on retrieval, they were infused into the hippocampus 10 min prior to STM testing at 3 h (see above) or 10 min before LTM testing at 24 h. In addition, the effect of Go 6976 and Go 7874 was studied on general activity measured in an open field, and on performance in an elevated plus maze. Results: STM was suppressed by 4.6 nM GB 6976 given 10 min before or 50 min after training. LTM was cancelled by the higher dose of the two compounds given 10 min before, or 50 min or 110 min after training. None of the two compounds infused 170 min post-training affected the retrieval of STM measured 10 min later. However, both compounds given 10 min before testing inhibited the retrieval of LTM measured at 24 h. This effect cannot be attributed to influences on locomotor activity or anxiety levels, since the drugs had no effect on performance in the open field but were mildly "anxiogenic" (pro-conflict) and reduced the number of entries into open and closed arms and rearings. Conclusions: LTM consolidation requires in part alpha- and/or beta I-PKC and in part other PKC isoforms. STM formation requires instead only alpha and/or beta I PKC and during a more limited period of time. In addition, PKC appears not to be necessary for the retrieval of STM, but is crucial for the retrieval of LTM. These findings further point to a biochemical separation of STM and LTM, as ascertained in numerous previous studies.