5-HT6 Receptor Antagonist Ameliorates Cognitive Dysfunction After Temporal Lobe Epilepsy Via Inhibits Aberrant Hippocampal Neurogenesis

Objective:Temporal lobe epilepsy(TLE)is a common type of epilepsy.Long-term seizures can lead to cognitive impairments,which may be induced by aberrant hippocampal neurogenesis.It has been illustrated that 5-HT6 receptor(5-HT6R)antagonist could improve the cognitive decline in schizophrenia and Alzheimer disease.Moreover,it is worthwhile to be noted that 5-HT6R was up-regulated both in TLE patients and animal model.The administration of 5-HT6R antagonist could decrease the seizure frequency.However,the effects of 5-HT6R on cognitive dysfunction after epilepsy remained unclear.This study therefore aims to investigate the roles of 5-HT6R in the cognitive deficits associated with epilepsy and the potential mechanisms.Methods:Male Sprague-Dawley rats(200-250g)were involved in our study.All the ratswere randomly divided into three groups:negative control group(Con),TLE group(TLE)and SB271046 treated group(TLE-SB)or PP2 treated group(TLE-PP2).Rats were given pilocarpine to induce epilepsy.Rats with continuous stage 5 seizures for 2h were enrolled in our experiment.Three days later,the rats in TLE-SB group were given SB271046(highly selective 5-HT6R antagonist,10mg/kg,orally)till the day before water maze test or the end of the second week.And the rats in TLE-PP2 group were injected with PP2(inhibitor of Fyn,1mg/kg,i.p.)three days after status epilepsy till the end of the second week.Intraperitoneal injection of 50 mg/kg BrdU for continuous seven days was utilized to measure cellular proliferation.Morris water maze was used to detect the special learning of all the rats.We used immunohistochemistry and immunofluorescence to test the aberrant neurogenesis and Western blot was used to test the expression of 5-HT6R,p-Fyn,p-ERKl/2,t-Fyn,t-ERK1/2.Results:Our results showed that the ability of special learning and memory of rats in TLE group were extremely reduced compared with the rats in Con group.After the administration of SB271046,the rats showed improved ability of special learning and memory.The results of immunohistochemistry and immunofluorescence revealed that the newly generated neural cells were increased obviously after epilepsy both in subgranular zone(SGZ)and hilar region of the hippocampus.5-HT6R antagonist SB271046 could remarkably decrease the number of newly generated neural cells.Further study showed that SB271046 could inhibit 5-HT6R signal pathway and then reduced phosphorylation of Fyn(p-Fyn)and ERK1/2(p-ERK1/2).Conclusion:In conclusion,our results showed that the administration of SB271046 could improve special learning and memory impairment induced by epilepsy.The effects of SB271046 on special learning and memory impairment after epilepsy might be mediated via inhibiting the aberrant neurogenesis associated with 5-HT6R/p-Fyn/p-ERK1/2 pathway.