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An immunocytochemical examination of the rabbit hippocampus was done to determine which of the Ca 21 -dependent protein kinase C (PKC) isoforms (PKCa, -bI, -bII, or -g) are involved in associative learning. The hippocampally dependent trace eyeblink conditioning task was used for behavioral training, and pseudoconditioned and naive animals served as controls. Significant increases (P F 0.05) in staining intensity were found with antibodies reactive with the catalytic or the regulatory domain of PKCg in conditioned animals compared with naive and pseudoconditioned subjects at a 24-h post-conditioning time point. The increase was found in CA1 and CA3 pyramidal cell bodies, in apical dendrites and the proximal part of the basilar dendrites, and in cell bodies of dentate granule cells. In contrast, no conditioning-specific changes were found for PKCa, -bI, or -bII in hippocampal neurons. The increase in PKCg immunoreactivity (ir) was significantly less (P F 0.05) in poor learners than in good learners. The correlation between the degree of PKCg-ir and the total number of conditioned responses across training sessions was both positive and significant. These results suggest that PKCg is the major Ca 21 -dependent PKC isoform involved in hippocampal neurons during acquisition of associative memories. Immunoblots revealed no conditioning-induced increase in the total amount or translocation of PKCg at the 24-h time point, and no proteolytic PKC fragments were observed. In agreement with the Western blot data, PKC activity did not differ among naive, pseudoconditioned, and trace conditioned animals. The conditioning-induced increase in antibody binding to the g-isoform must therefore be due to an increased access to the antigenic site(s) as a result of alteration in the tertiary structure of PKCg or in quaternary interactions of PKCg in situ.

The cholinergic system is known to show deterioration during aging and Alzheimer's disease (AD). In response, a therapeutic approach to AD has been to attempt to compensate for the decrease in central cholinergic function by potentiating the activity of the remaining intact cholinergic cells with cholinesterase (ChE) inhibitors. In this study treatment with the long-lasting ChE inhibitor metrifonate facilitated acquisition and retention of eyeblink conditioning in aging rabbits. Metrifonate treatment resulted in steady-state, dose-dependent acetylcholinesterase (AChE) inhibition in red blood cells. Maximal behavioral efficacy was achieved with AChE inhibition of approximately 40%, with no further improvements resulting from increased levels of inhibition. Metrifonate was behaviorally effective in the absence of the severe side effects that can plague ChE inhibitors, supporting metrifonate as a possible treatment for the cognitive deficits resulting from normal aging and AD.

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