Lrp4 in hippocampal astrocytes serves as a negative feedback factor in seizures

Abstract

Background 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. 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. Results We 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. Conclusions These 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.

Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling

“…1 F). These results suggest that Lrp4 mutation in the brain decreases seizure susceptibility, in line with previous reports [ 25 , 26 ]. We then treated mice with diazepam 1 h after SE onset to terminate seizure activity.…”

“…In our previous study, we have reported that Lrp4 is enriched in the astrocytes of hippocampal region, where it modulates excitatory presynaptic transmitter release and synaptic plasticity via regulation of astrocytic ATP release [ 25 ]. Interestingly, Lrp4 seems vital to seizure threshold as Lrp4 deletion caused delayed seizure induced by pilocarpine [ 25 ], which is further confirmed by a recent paper [ 26 ]. These observations suggest that Lrp4 in astrocyte is required for the regulation of seizure susceptibility.…”

Ablation of Lrp4 in Schwann Cells Promotes Peripheral Nerve Regeneration in Mice

“…The Lrp4-LacZ mice were described previously [ 27 , 28 ]. Lrp4 flox/flox ( Lrp4 f/f ) mice [ 9 ] were crossed with Dhh-cre mice (Jax stock #012929) to generate Dhh::Cre ; Lrp4 f/f mice ( Dhh-Lrp4 −/− , referred to as cKO hereafter).…”