Abstract
Epilepsy is associated with aberrant neurogenesis in the hippocampus and may underlie the development of hereditary epilepsy. In the present study, we analyzed the differentiation fate of neural progenitor cells (NPC), which were isolated from the hippocampus of embryos of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic epilepsy. NPCs from embryos of Wistar rats were used as the control. We found principal differences between Wistar and KM NPC in unstimulated controls: Wistar NPC culture contained both gamma-aminobutyric acid (GABA) and glutamatergic neurons; KM NPC culture was mainly represented by glutamatergic cells. The stimulation of glutamatergic differentiation of Wistar NPC resulted in a significant increase in glutamatergic cell number that was accompanied by the activation of protein kinase A. The stimulation of KM NPC led to a decrease in immature glutamatergic cell number and was associated with the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B/ glycogen synthase kinase 3 beta (Akt/GSK3β), which indicates the activation of glutamatergic cell maturation. These results suggest genetically programmed abnormalities in KM rats that determine the glutamatergic fate of NPC and contribute to the development of audiogenic epilepsy.
Highlights
Audiogenic epilepsy is a form of reflex epilepsy and its etiology is mainly hereditary, both in human and animal [1,2,3]
After stimulation of glutamatergic differentiation, we observed the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Akt signaling in KM neural progenitor cells (NPC), while in Wistar NPC we revealed activation of protein kinase A (PKA)
To investigate the effectiveness of glutamatergic differentiation protocol, we carried out immunofluorescent detection of vesicular glutamate transporters 1 and 2 (VGLUT1/2) and glutamate decarboxylases 65 and 67 (GAD65/67), which are markers of glutamatergic and GABAergic neurons, respectively
Summary
Audiogenic epilepsy is a form of reflex epilepsy and its etiology is mainly hereditary, both in human and animal [1,2,3]. Observations of patients with epilepsy and the results of experimental modeling of seizures indicate that epileptiform activity stimulates proliferation of neural progenitors in the subgranular layer of the dentate gyrus [7,8,9,10]. Part of these newborn cells migrates to the hilus and differentiates into ectopic excitatory glutamatergic neurons that exhibit stable hyperactivity and tend to synchronize with Cornu Ammonis area 3 (CA3) pyramid cells of the hippocampus [10,11]. The inhibition of aberrant neurogenesis caused by status epilepticus significantly reduced the frequency and severity of seizures [12,13]
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