Abstract
BackgroundEpilepsy is characterized by the typical symptom of seizure, and anti-seizure medications are the main therapeutic method in clinical, but the effects of these therapy have not been satisfactory. To find a better treatment, it makes sense to further explore the regulatory mechanisms of seizures at genetic level. Lrp4 regionally expresses in mice hippocampus where is key to limbic epileptogenesis. It is well known that neurons release a high level of glutamate during seizures, and it has been reported that Lrp4 in astrocytes down-regulates glutamate released from neurons. However, it is still unclear whether there is a relationship between Lrp4 expression level and seizures, and whether Lrp4 plays a role in seizures.ResultsWe found that seizures induced by pilocarpine decreased Lrp4 expression level and increased miR-351-5p expression level in mice hippocampus. Glutamate reduced Lrp4 expression and enhanced miR-351-5p expression in cultured hippocampal astrocytes, and these effects can be partially attenuated by AP5. Furthermore, miR-351-5p inhibitor lessened the reduction of Lrp4 expression in glutamate treated hippocampal astrocytes. Local reduction of Lrp4 in hippocampus by sh Lrp4 lentivirus injection in hippocampus increased the threshold of seizures in pilocarpine or pentylenetetrazol (PTZ) injected mice.ConclusionsThese results indicated that high released glutamate induced by seizures down-regulated astrocytic Lrp4 through increasing miR-351-5p in hippocampal astrocytes via activating astrocytic NMDA receptor, and locally reduction of Lrp4 in hippocampus increased the threshold of seizures. Lrp4 in hippocampal astrocytes appears to serve as a negative feedback factor in seizures. This provides a new potential therapeutic target for seizures regulation.
Highlights
Epilepsy is characterized by the typical symptom of seizure, and anti-seizure medications are the main therapeutic method in clinical, but the effects of these therapy have not been satisfactory
Seizures induced by pilocarpine decreased Low-density lipoprotein receptor-related protein 4 (Lrp4) expression in hippocampus in vivo To find out whether seizures could influence Lrp4 expression in hippocampal astrocytes, epileptic seizures were induced in adult mouse by pilocarpine injection (300 mg/kg, i.p.) [19]
The results showed that seizures induced by pilocarpine significantly increased the relative level of Bdnf mRNA in hippocampus at each time point after injection, compared to control mice (Additional file 1: Fig. S1A), which is in agreement with previous observations [20, 21]
Summary
Epilepsy is characterized by the typical symptom of seizure, and anti-seizure medications are the main therapeutic method in clinical, but the effects of these therapy have not been satisfactory. Lrp regionally expresses in mice hippocampus where is key to limbic epileptogenesis. It is well known that neurons release a high level of glutamate during seizures, and it has been reported that Lrp in astrocytes down-regulates glutamate released from neurons. It is still unclear whether there is a relationship between Lrp expression level and seizures, and whether Lrp plays a role in seizures. The definition of Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. In the clinical, it is usually practically applied as having two unprovoked seizures > 24 h apart [2]. The question here is whether there is a relationship between Lrp expression and seizures, and whether Lrp plays a role in seizures
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