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Mossy fiber mis-pathfinding and semaphorin reduction in the hippocampus of α-CaMKII hKO mice
Soichiro Nakahara1, Shinichi Miyake1, Katsunori Tajinda1
1CNS, Astellas Res. Inst. of America LLC, 8045 Lamon Avenue, Skokie, IL 60077, USA.
Abstract:
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.
Insights
Alpha-isoform of calcium/calmodulin-dependent protein kinase II (α-CaMKII) deficiency in mice causes immature dentate granule cells and working memory deficits. Mossy fiber mis-guidance, linked to semaphorin-3A, may contribute to these immature phenotypes.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Alpha-isoform of calcium/calmodulin-dependent protein kinase II (α-CaMKII) deficiency in adult mice leads to immature dentate granule cells, characterized by dendritic abnormalities and altered neuron marker expression.
- Heterozygous α-CaMKII inactivation in mice results in behavioral deficits, notably working memory impairments, mirroring those seen in psychiatric disorders.
- The topological regulation of mossy fibers, crucial for neuronal transmission and behavior, in α-CaMKII-deficient animals remains poorly understood.
Purpose of the Study:
- To investigate the role of semaphorin signaling in regulating mossy fiber pathfinding in α-CaMKII heterozygous knock-out (hKO) mice.
- To determine if semaphorin signaling is involved in the observed axonal morphogenesis defects in α-CaMKII hKO mice.
Main Methods:
- Immunohistochemical characterization of mossy fiber projections in the brains of α-CaMKII hKO mice.
- Analysis of semaphorin-3A expression levels in the dentate gyrus of α-CaMKII hKO mice.
Main Results:
- Mossy fibers in α-CaMKII hKO mice aberrantly invaded the stratum oriens, in addition to the normal CA3 stratum lucidum.
- A significant decrease in semaphorin-3A expression was observed in α-CaMKII hKO mice.
- These findings indicate a potential link between reduced semaphorin-3A and mossy fiber mis-guidance.
Conclusions:
- Mossy fiber mis-guidance, potentially mediated by semaphorin-3A dysregulation, is a key biomarker of dentate granule cell immaturity in α-CaMKII deficient mice.
- This axonal mis-guidance may contribute to the abnormal behavioral phenotypes, including working memory deficits, observed in these mice.
- Semaphorin signaling represents a potential therapeutic target for addressing neurodevelopmental deficits associated with α-CaMKII deficiency.
