Mossy fiber mis-pathfinding and semaphorin reduction in the hippocampus of α-CaMKII hKO mice.

Recent evidence indicates that alpha-isoform of calcium/calmodulin-dependent protein kinase II (α-CaMKII) deficiency in adult mice induces phenotypic immaturity of dentate granule cells, defined by dendritic disturbance and aberrant maturational neuron marker expression. Mice possessing a heterozygous inactivation of α-CaMKII display abnormal behavioral phenotypes, including working memory deficits similar to those observed in psychiatric patients. Currently, how the guidance of mossy fibers, the axonal projections of granule cells, are topologically regulated in the dentate gyrus of α-CaMKII deficient animals is not well understood, even though axonal morphogenesis is a key factor for modulating neuronal transmission and animal behavior. In the present study, we explored the involvement of semaphorin signaling, a well-studied guidance factor in mossy fiber pathfinding, in α-CaMKII heterozygous knock-out mice (α-CaMKII hKO mice). Using immunohistochemical characterization, we found mossy fibers invade not only the CA3 stratum lucidum region, but also stratum oriens region where mossy fibers do not usually bundle. Furthermore, α-CaMKII hKO mice have decreased semaphorin-3A expression. These results suggest mossy fiber mis-guidance, possibly regulated by semaphorin-3A, is one of the biomarkers reflecting immaturity in dentate granule cells, possibly contributing to abnormal behavioral phenotypes.