title: A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression.
abstract: Unverricht-Lundborg disease (EPM1), the most common progressive myoclonic epilepsy, is associated with a defect of cystatin B (CSTB), a protease inhibitor. We used CSTB knockout mice to test the hypothesis that EPM1 onset is related to a latent hyperexcitability and that progression depends on higher susceptibility to seizure-induced cell damage. Hippocampal slices prepared from CSTB-deficient mice were hyperexcitable, as they responded to afferent stimuli in CA1 with multiple population spikes and kainate perfusion provoked the appearance of epileptic-like activity earlier than in WT mice. This hyperexcitability may depend on loss of inhibition, because the density of GABA-immunoreactive cells was reduced in the hippocampus of CSTB knockouts. In vivo, CSTB-deficient mice treated with kainate displayed increased susceptibility to seizures, with shorter latency to seizure onset and increased seizure severity compared with WT littermates. Furthermore, a greater degree of neuronal damage was observed in CSTB-deficient than in WT mice after seizures of identical grade, indicating increased susceptibility to seizure-induced cell death.
authors.affiliation: Division of Neurophysiology and Epileptology, Neurological Institute C. Besta via Caloria 11, 20133 Milan, Milan, Italy. franceschetti@istituto-besta.it
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Giulio
authors.initials: G
authors.lastname: Sancini
authors.forename: Andrea
authors.initials: A
authors.lastname: Buzzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchini
authors.forename: Beatrice
authors.initials: B
authors.lastname: Paradiso
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Magnaghi
authors.forename: Carolina
authors.initials: C
authors.lastname: Frassoni
authors.forename: Maia
authors.initials: M
authors.lastname: Chikhladze
authors.forename: Giuliano
authors.initials: G
authors.lastname: Avanzini
authors.forename: Michele
authors.initials: M
authors.lastname: Simonato
mesh_terms: D000818:Animals; D055313:Cystatin B; D015891:Cystatins / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004594:Electrophysiology; D004831:Epilepsies, Myoclonic / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000473:pathology / Q000502:physiology; D007608:Kainic Acid; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009410:Nerve Degeneration / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009924:Organ Culture Techniques; D020194:Unverricht-Lundborg Syndrome / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*
chemical_list: C524992:Cstb protein, mouse; D015891:Cystatins; D018690:Excitatory Amino Acid Agonists; D055313:Cystatin B; D007608:Kainic Acid