A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression.
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.
Franceschetti
Silvana
S
Division of Neurophysiology and Epileptology, Neurological Institute C. Besta via Caloria 11, 20133 Milan, Milan, Italy. franceschetti@istituto-besta.it
Sancini
Giulio
G
Buzzi
Andrea
A
Zucchini
Silvia
S
Paradiso
Beatrice
B
Magnaghi
Giuseppina
G
Frassoni
Carolina
C
Chikhladze
Maia
M
Avanzini
Giuliano
G
Simonato
Michele
M
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*
C524992:Cstb protein, mouse; D015891:Cystatins; D018690:Excitatory Amino Acid Agonists; D055313:Cystatin B; D007608:Kainic Acid