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 M-current 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 M-channel 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.
Highlights
Cognitive impairment is common in temporal lobe epilepsy (TLE) (Huang et al, 2019), and the typical characteristic of pathological changes in TLE is hippocampal sclerosis, including neuronal loss in the CA3/CA1/DG region, glial proliferation, and abnormal mossy fiber sprouting (Schmeiser et al, 2017; Prada Jardim et al, 2018; Tai et al, 2018)
Our current study demonstrated that spontaneous recurrent seizures (SRSs) increased the protein expression of 5-HT6 receptor (5-HT6R) and decreased both the RNA of KCNQ2 and protein of KCNQ2 in hippocampus
In the pilocarpine-induced epileptic rat model, SB271046 rescued the aberrant M-current, reduced the excitability of the hippocampal pyramidal neurons, and improved the impaired Long-term potentiation (LTP), which were reversed by XE991, which selectively inhibits M-current
Summary
Cognitive impairment is common in temporal lobe epilepsy (TLE) (Huang et al, 2019), and the typical characteristic of pathological changes in TLE is hippocampal sclerosis, including neuronal loss in the CA3/CA1/DG region, glial proliferation, and abnormal mossy fiber sprouting (Schmeiser et al, 2017; Prada Jardim et al, 2018; Tai et al, 2018). Neuronal loss and lesions in chronic spontaneous recurrent seizures (SRSs) occur in CA3/CA1/DG over the course of TLE (Sloviter, 1994; Bannerman et al, 2014). The loss of neurons in TLE is spread and brings about hippocampus-dependent learning and memory impairment, which could be detected via LTP.
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