Dysfunction of GABAA receptors (GABAARs) is a prominent factor affecting intractable epilepsy. Plic-1, an ubiquitin-like protein enriched in the inhibitory synapses connecting GABAARs and the ubiquitin protease system (UPS), plays a key role in the modification of GABAAR functions. However, the relationship between Plic-1 and epileptogenesis is not known. In this study, we aimed to investigate Plic-1 levels in patients with temporal lobe epilepsy, as well as the role of Plic-1 in regulating onset and progression of epilepsy in animal models. We found that Plic-1 expression was significantly decreased in epileptic patients as well as pilocarpine and pentylenetetrazol (PTZ)-induced rat epileptic models. Intra-hippocampal injection of PePα peptide, which disrupts Plic-1 binding to GABAARs, significantly shortened the latency of seizure onset, increased seizure severity and duration in these two epileptic models. Over-expressed Plic-1 through lentivirus transfection into a PTZ model resulted in a reduction of both seizure severity and generalized tonic–clonic seizure duration. Whole cell clamp recordings revealed that PePα peptide decreased miniature inhibitory postsynaptic current (mIPSC) while overexpressed Plic-1 increased miniature inhibitory postsynaptic current (mIPSC) in the pyramidal neurons of the hippocampus. These effects can be blocked by PTX, a GABAAR inhibitor. Our results indicate that Plic-1 plays an important role in managing epileptic seizures by enhancing seizure inhibition through regulation of GABAARs at synaptic sites.
- Copyright 2015 The Author(s)
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