Previous studies from our laboratory have indicated that genetic differences in spatial learning performance can be revealed using the Morris water task. C57BL/6 mice performed relatively well while DBA/2 mice perform poorly on the task. These strains and many recombinant inbred strains generated from a C57 X DBA/2 cross show variation in spatial learning performance and this variation is significantly correlated to hippocampal protein kinase C activity. Protein kinase C (PKC) is activated via generation of diacylglycerol during phosphatidyl inositol turnover, an important second messenger in brain. Because of the central role of PKC in the brain, it provides an important substrate for further investigation using a genetic approach. We purpose to examine the role of hippocampal PKC in determining genetic differences in learning performance from several perspectives. The nature of the learning deficit in DBA mice will be examined further using behavioral approaches. The question of whether protein kinase C activity changes as a function of training will also be investigated. Biochemical studies will be designed to elucidate the nature of the strain differences in hippocampal PKC activity by investigating the isozymic patterns in C57 and DBA mice. Molecular genetic studies will examine the DNA sequence of the major PKC genes from C57 and DBA mice; the expression of these genes in brain and potential effects of training on gene expression; and the regional localization of this expression will be examined by in situ hybridizations. The results of the proposed studies should allow a more complete assessment of the nature of spatial learning performance deficits, and provide information as to approaches for the future correction of such deficits. Furthermore, the role of hippocampal PKC in learning and memory processes should be delineated.
