title: Plic-1, a new target in repressing epileptic seizure by regulation of GABAAR function in patients and a rat model of epilepsy.
abstract: Dysfunction of γ-aminobutyric acid A (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 the present 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 patients with epilepsy as well as pilocarpine- and pentylenetetrazol (PTZ)-induced rat epileptic models. Intrahippocampal injection of the PePα peptide, which disrupts Plic-1 binding to GABAARs, significantly shortened the latency of seizure onset, and increased the seizure severity and duration in these two epileptic models. Overexpressed Plic-1 through lentivirus transfection into a PTZ model resulted in a reduction in both seizure severity and generalized tonic-clonic seizure duration. Whole-cell clamp recordings revealed that the PePα peptide decreased miniature inhibitory postsynaptic currents (mIPSCs) whereas overexpressed Plic-1 increased mIPSCs in the pyramidal neurons of the hippocampus. These effects can be blocked by picrotoxin, 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.
authors.affiliation: Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Zengyou
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York, NY, U.S.A.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China fyp@163.com.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000071183:Autophagy-Related Proteins; D058256:Brain Waves / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005822:Genetic Vectors; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials; D016086:Lentivirus / Q000235:genetics; D008297:Male; D055369:Miniature Postsynaptic Potentials; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010433:Pentylenetetrazole; D010862:Pilocarpine; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014161:Transduction, Genetic; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000927:Anticonvulsants; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D058787:GABA-A Receptor Antagonists; D018832:Molecular Chaperones; D009842:Oligopeptides; D011963:Receptors, GABA-A; C107792:UBQLN1 protein, human; C575873:Ubqln1 protein, rat; D010862:Pilocarpine; D010433:Pentylenetetrazole
keywords: GABAARs; anticonvulsant; epilepsy; protein linking integrin-associated protein to cytoskeleton 1 (ubiquitin-like protein 1 or Plic-1); seizure.