5-HTR6 Involves In Mossy Fiber Sprouting (MFS) In Lithium-pilocapine Induced Epiletptic Rats

Objects Mossy fiber sprouting(MFS) is a common synaptic plasticity in human temporal lobe epilepsy and in various animal models that can promote spontaneous recurrent seizures; however the underlying mechanisms still remain unclear. 5-HTR6 blockade has a beneficial effect on neuronal synaptic that plays important roles in the neurological diseases, including epilepsy. We investigated 5-HT6 R involved in the development of MFS by activating the extracellular signal regulated kinase1/2 via Fyn-dependent pathway that modulated the expression of GAP-43 m RNA in pilocapine-induced epiletptic rats.Methods In the first part of the experiment Adult male Sprague-Dawley rats were divided into two groups: control(n=18) and epileptic(n=54). Li Cl-pilocarpine was intraperitoneally(i.p.) injected to induce status epilepticus(SE). the behavior of the rats were observed after seizure.In the second part of the experiment, the epileptic rats(n=126)were divided into seven sub-groups(n=18) and intracerebroventricularly injected with the same volume of SB-271046(100 ?g/kg); PP2(50 ?g/kg); PD-98059(30 ?g/kg); SB-271046(100 ?g/kg) + PP2(50 ?g/kg); SB-271046(100 ?g/kg) +PD-98059(30 ?g/kg), all dissolved in 10% DMSO; for 7 days. MFS was detected using Timm's staining.Then, expression levels of HTR6, Fyn and p-ERK1/2 were determined by western blotting, and GAP-43 m RNA expression was evaluated by RT-PCR.Results:After SE, over-expressed HTR6 and MFS became more and more obvious compared to control group and peaked at 4 weeks, Levels of 5-HTR6, Fyn, p-ERK1/2 and GAP-43 m RNA increased at the same pattern as MFS. The antagonists of 5-HTR6,Fyn and p-ERK1/2 reversed MFS and decreased the expression of p-ERK1/2 and GAP-43 m RNA. Interestingly, SB271046 adding PPI or PD98059 further reversed and the latter at the most degree.Conclusion:We observed over-expressed HTR6 and obvious MFS in pilocarpine-induced chronic epileptic rats and demonstrated HTR6 may involve in the progression of MFS through activating p-ERK1/2 via Fyn-dependant pathway modulating GAP-43 expression.Further study needs to shed light on other signaling pathways to GAP-43.