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Involvement of CaMKIV in neurogenic effect with chronic fluoxetine treatment
Ning Song1, Shin Nakagawa, Takeshi Izumi
1Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Abstract:
Calcium-calmodulin dependent protein kinase IV (CaMKIV) is a protein kinase that has been suggested to participate in fluoxetine (FLX)-induced phosphorylation of cyclic AMP-response element binding protein (CREB). CREB is a key transcription factor in adult neurogenesis. The present study aimed at evaluating whether CaMKIV is involved in adult hippocampal neurogenesis with FLX treatment. Effects of chronic FLX on hippocampal cell proliferation, survival and phenotypes were assessed using bromodeoxyuridine (BrdU) immunohistochemistry or BrdU/neuronal nuclei (NeuN)/S100β immunofluorescence staining in wild-type (WT) and CaMKIV knockout (KO) mice. Expression and phosphorylation of CaMKIV and CREB were assessed using RT-PCR and Western blotting. The behavioural action with FLX was assessed in the novelty suppressed feeding test (NSF), which is considered neurogenesis-dependent. CaMKIV KO mice have reduced cell proliferation, but not survival in the dentate gyrus of hippocampus with chronic treatment of FLX when compared to wild littermates. Phenotype analysis showed that most newborn cells matured into neurons. Phosphorylation of CaMKIV was up-regulated in WT mice and phosphorylation of CREB was impaired in CaMKIV KO mice after FLX treatment. The behavioural effects of FLX in NSF were similar in both types. These data suggest that CaMKIV is involved in some aspects of FLX-promoting hippocampal neurogenesis.
Insights
Calcium-calmodulin dependent protein kinase IV (CaMKIV) influences fluoxetine-induced neurogenesis. CaMKIV knockout mice show reduced hippocampal cell proliferation, impacting CREB phosphorylation but not overall antidepressant-like behavior.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Calcium-calmodulin dependent protein kinase IV (CaMKIV) is implicated in fluoxetine (FLX)-induced cyclic AMP-response element binding protein (CREB) phosphorylation.
- CREB is a critical transcription factor for adult neurogenesis.
Purpose of the Study:
- To investigate the role of CaMKIV in adult hippocampal neurogenesis following FLX treatment.
- To assess the impact of CaMKIV deficiency on FLX's effects on neurogenesis and behavior.
Main Methods:
- Utilized wild-type (WT) and CaMKIV knockout (KO) mice.
- Assessed hippocampal cell proliferation, survival, and phenotypes using bromodeoxyuridine (BrdU) immunohistochemistry and immunofluorescence (BrdU/NeuN/S100β).
- Analyzed CaMKIV and CREB expression and phosphorylation via RT-PCR and Western blotting; evaluated FLX's behavioral effects in the novelty suppressed feeding (NSF) test.
Main Results:
- CaMKIV KO mice exhibited reduced hippocampal cell proliferation but not survival after chronic FLX treatment compared to WT mice.
- Most newly generated cells differentiated into neurons.
- FLX treatment upregulated CaMKIV phosphorylation in WT mice and impaired CREB phosphorylation in CaMKIV KO mice.
- Behavioral responses to FLX in the NSF test were comparable between WT and CaMKIV KO mice.
Conclusions:
- CaMKIV plays a role in specific aspects of FLX-promoted adult hippocampal neurogenesis.
- CaMKIV is involved in regulating cell proliferation during FLX treatment.
- Despite effects on neurogenesis markers, CaMKIV deficiency did not alter the overall behavioral outcomes of FLX in the NSF test.
