title: Viral clostridial light chain gene-based control of penicillin-induced neocortical seizures.
abstract: Restraining excitatory neurotransmission within a seizure focus provides a nondestructive treatment strategy for intractable neocortical epilepsy. Clostridial toxin light chain (LC) inhibits synaptic transmission by digesting a critical vesicle-docking protein, synaptobrevin, without directly altering neuronal health. This study tests the treatment efficacy of adenoviral vector delivered LC (AdLC) on a model of seizures in rats induced by motor cortex penicillin (PCN) injection. LC expression significantly reduced electroencephalogram (EEG) frequency, amplitude, duration, and latency compared to control groups injected with either an adenoviral vector bearing green fluorescent protein (AdGFP) or phosphate buffered solution (PBS). Correspondingly, LC gene expression improved behavioral manifestations including seizure severity and latency. There was no statistical difference in motor function before and after vector administration between treatment and control groups. Histological analysis revealed spatially discrete LC expression with corresponding synaptobrevin depletion in the cortex surrounding the injection site. Thus, vector-mediated LC gene delivery is capable of improving both the EEG and behavioral manifestations of PCN-induced focal neocortical seizures through synaptobrevin depletion.
authors.affiliation: Departments of Neuroscience and Neurosurgery, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Teng
authors.forename: Thais
authors.initials: T
authors.lastname: Federici
authors.forename: Imad
authors.initials: I
authors.lastname: Najm
authors.forename: Stephan
authors.initials: S
authors.lastname: Chabardes
authors.forename: Michael
authors.initials: M
authors.lastname: Moffitt
authors.forename: Andreas
authors.initials: A
authors.lastname: Alexopoulos
authors.forename: Jonathan
authors.initials: J
authors.lastname: Riley
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Boulis
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight / Q000187:drug effects; D004279:DNA, Viral / Q000235:genetics*; D004569:Electroencephalography; D015870:Gene Expression; D015316:Genetic Therapy; D008297:Male; D009044:Motor Cortex / Q000187:drug effects; D010406:Penicillins / Q000008:administration & dosage / Q000633:toxicity*; D050683:R-SNARE Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D019076:Transgenes / Q000235:genetics
chemical_list: D004279:DNA, Viral; D010406:Penicillins; D050683:R-SNARE Proteins