The Antagonism of 5-HT6 Receptor Attenuates Current-Induced Spikes and Improves Long-Term Potentiation via the Regulation of M-Currents in a Pilocarpine-Induced Epilepsy Model

Abstract

Recent studies have documented that reduced M-current promotes epileptogenesis and attenuates synaptic remodeling. Neurite growth is closely related to the level of 5-HT6 receptor (5-HT6R) in the central nervous system. However, little research is available regarding the relation between 5-HT6R and M-current and the role of 5-HT6R in Mcurrent regulation. Herein, we found that the expression of 5-HT6R was notably increased and the expression of KNCQ2/3, the main components of the M channel, was decreased in a time-dependent manner in pilocarpine-induced chronic epileptic hippocampus. Interestingly, antagonism of 5-HT6R by SB271046 upregulated the expression of KCNQ2 but not KCNQ3. SB271046 greatly alleviated excitatory/inhibitory imbalance and improved the impaired LTP in the chronic epileptic hippocampus. Further mechanism exploration revealed that the above effects of SB271046 can be reversed by the Mchannel inhibitor XE991, which also confirmed that SB271046 can indeed improve abnormal M current. These data indicate that the antagonism of 5-HT6R may decrease the excitability of hippocampal pyramidal neurons in chronic epileptic rats and improve the impaired long-term potentiation by upregulating the expression of KCNQ2 in the M-channel.

Pharmacological inhibition of S6K1 rescues synaptic deficits and attenuates seizures and depression in chronic epileptic rats

“…As previously described, status epilepticus (SE) was induced by the administration of lithium‐pilocarpine following our previous study (see Supporting Information ). 15 Repeated doses (≤3) of pilocarpine hydrochloride (30 mg/kg, i.p., Sigma–Aldrich, P6503) were given to the rat every 30 min until the emergence of SE (Stage IV–V on Racine's scale). 16 More than 60 min after the onset of SE, diazepam (10 mg/kg, i.p.)…”

Potassium channels and epilepsy

“…Their findings demonstrate that these mutations are subject to degradation through the ubiquitin‐independent proteasome pathway, a cellular mechanism by which incomplete dominant‐negative mutations of KCNQ2 cause epilepsy. Zhou et al 69 found that the inhibition of 5‐HT6R upregulated the expression of KCNQ2 attenuated current‐induced spikes and improved long‐term potentiation via the regulation of M‐currents in a pilocarpine‐induced epilepsy model. Their study indicated that the 5‐HT6 receptor is a new target for intervention in KCNQ2 ‐induced epilepsy.…”