| Abstract No.: | C-A3016 |
| Country: | USA |
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| Title: | CYCLIN DEPENDENT KINASE 5 (CDK5) IS NECESSARY FOR NEURONAL MATURATION WITHIN THE ADULT HIPPOCAMPUS |
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| Authors/Affiliations: | 1 Diane Lagace*; 1 David Benavides; 1 Janice Kansy; 1 James Bibb; 1 Amelia Eisch;
1 University of Texas Southwestern Medical Center, Dallas, TX, USA
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| Content: | Objective: Delineation of the intrinsic and microenvironmental factors that influence proliferation, differentiation, and maturation of neural precursors is essential to the creation of novel treatments for neurological and neuropsychiatric disorders that may involve altered adult neurogenesis. Based on the hypothesis that neurogenesis during development and adulthood share some common intracellular signal transduction pathways, we evaluated the role of the neuronal protein kinase Cdk5 and its neuronal specific activating cofactors p35 and p39 in the generation of new neurons in the adult dentate gyrus.
Material and Methods: Proliferation and neurogenesis were assessed in a variety of transgenic mouse models that have reduced levels of Cdk5, p35 or p39 within the hippocampus and/or progenitor cells, as well as in mice with reduced levels of Cdk5 due to in vivo adeno-associated virus (AAV)-Cre recombinase mediated gene deletion.
Results: Using a novel monoclonal Cdk5 antibody, we demonstrate in vivo immunohistochemical distribution of Cdk5 within immature (doublecortin-immunoreactive, DCX-IR) and mature (NeuN-IR) neurons within the neurogenic niche of the adult hippocampus. Inducible ablation of Cdk5 from the heterogeneous cell population of adult progenitor cells and their progeny in the Nestin-CreERT2/R26R-YFPfloxed Cdk5 mice demonstrate Cdk5 has a cell-autonomous role for cell maturation of immature neurons (DCX-IR) in the adult subgranular zone. In addition, three independent mouse models (CamKII-Cre/floxed Cdk5 mice, p35 embryonic KO mice, AAV-Cre transfected R26R-YFP/floxed Cdk5 mice) demonstrate Cdk5 expression within the mature granule cells has a non-cell autonomous role in the formation of immature neurons (DCX-IR), independent of effects on the number of proliferating cells.
Conclusion: The convergent data from these multiple approaches demonstrate Cdk5 in the neurogenic niche is critical for the maturation, but not proliferation, of neurons in the postnatal hippocampus. Cdk5 alters neurogenesis through a cell autonomous mechanism mediated by Cdk5 expression in immature neurons, as well as a non-cell autonomous mechanism mediated by Cdk5 expression in mature neurons. |
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