Abstract
It is well known that epileptogenesis is accompanied with the aberrations in the hippocampal neurogenesis in human as well as in epileptic animals. The Krushinsky--Molodkina (KM) rats genetically prone to audiogenic seizure were recruited in the experiments. Neuronal stem cells (NSC) isolated from the hippocampus of KM rats at the 14--17 days of postnatal development, which corresponds the final stage for the development of the hippocampal neurogenic niche. NSC isolated from the hippocampus of Wistar rats were used as a control. The cells were incubated for 10 days in a medium supplemented with retinoic acid to stimulate neural differentiation. Previously we demonstrated that proliferation level of NSC KM was significantly lower in comparison with the NSC of Wistar rats, but neuronal differentiation rate of NSC KM was significantly higher. This research unravels the underlying molecular mechanisms. Analysis of Akt/GSK3b pathway demonstrated decreased expression of Akt that correlated with attenuation of phosphorylation level of GSK3b at Ser9 and decreased level of b-catenin. It is known that transcriptional factor CREB is one of the main substrates for Akt and on the other hand CREB tightly participates in the regulation of the cell proliferation. Obtained data revealed decreased activity of CREB in NSC KM in comparison to NSC Wistar that could mediate inhibition of cell cycle and potentiation the differentiation. Thus our results demonstrated that glutamatergic differentiation of NSC KM is mediated by AKT/GSK3b/b-catenin/CREB signaling pathway.
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