Unraveling mechanisms underlying epileptogenesis after brain injury is an unmet medical challenge. Although histopathological studies have revealed that reactive astrogliosis and tissue acidosis are prominent features in epileptogenic foci, their roles in epileptogenesis remain unclear. Here, we explored whether astrocytic acid-sensing ion channel-1a (ASIC1a) contributes to the development of chronic epilepsy. High levels of ASIC1a were measured in reactive astrocytes in the hippocampi of patients with temporal lobe epilepsy (TLE) and epileptic mice. Extracellular acidosis caused a significant Ca2+ influx in cultured astrocytes, and this influx was sensitive to inhibition by the ASIC1a-specific blocker psalmotoxin 1 (PcTX1). In addition, recombinant adeno-associated virus (rAAV) vectors carrying a GFAP promoter in conjunction with ASIC1a shRNA or cDNA were generated to suppress or restore, respectively, ASIC1a expression in astrocytes. Injection of rAAV-ASIC1a-shRNA into the dentate gyrus of the wide type TLE mouse model resulted in the inhibition of astrocytic ASIC1a expression and a reduction in spontaneous seizures. By contrast, rAAV-ASIC1a-cDNA restored astrocytic ASIC1a expression in an ASIC1a knock-out TLE mouse model and increased the frequency of spontaneous seizures. Taken together, our results reveal that astrocytic ASIC1a may be an attractive new target for the treatment of epilepsy.
Neurogenesis in the hippocampus is actively involved in neural circuit plasticity and learning function of mammals, but it may decrease dramatically with aging and aging-related neurodegenerative disorder Alzheimer's disease. Accumulating studies have indicated that Wnt/β-catenin signaling is critical in control of proliferation and differentiation fate of neural stem cells or progenitors in the hippocampus. In this study, the biological effects of low-dose radiation in stimulating Wnt/β-catenin signaling, neural stem cell proliferation and neurogenesis of hippocampus were interestingly identified by in vitro cell culture and in vivo animal studies. First, low-dose radiation (0.3Gy) induced significant increasing of Wnt1, Wnt3a, Wnt5a, and β-catenin expression in both neural stem cells and in situ hippocampus by immunohistochemical and PCR detection. Secondly, low-dose radiation enhanced the neurogenesis of hippocampus indicated by increasing proliferation and neuronal differentiation of neural stem cells, going up of nestin-expressing cells and BrdU-incorporation in hippocampus. Thirdly, it promoted cell survival and reduced apoptotic death of neuronal stem cells by flowcytometry analysis. Finally, Morris water-maze test showed behavioral improvement of animal learning in low-dose radiation group. Accordingly, detrimental influence on Wnt/β-catenin signaling or neurogenesis was confirmed in high-dose radiation (3.0Gy) group. Taken together, this study has revealed certain beneficial effects of low-dose radiation to stimulate neural stem cell proliferation, the neurogenesis of hippocampus and animal learning most possibly by triggering Wnt/β-catenin signaling cascades, suggesting its translational application role in devising new therapy for aging-related neurodegenerative disorders particularly Alzheimer's disease.
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