A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression

Neurobiol Dis. 2007 Mar;25(3):675-85. doi: 10.1016/j.nbd.2006.11.006. Epub 2006 Dec 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystatin B
  • Cystatins / genetics*
  • Disease Models, Animal
  • Disease Progression
  • Electrophysiology
  • Epilepsies, Myoclonic / chemically induced
  • Epilepsies, Myoclonic / etiology*
  • Epilepsies, Myoclonic / physiopathology*
  • Excitatory Amino Acid Agonists
  • Genetic Predisposition to Disease
  • Hippocampus / pathology
  • Hippocampus / physiology
  • Kainic Acid
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / pathology
  • Nerve Degeneration / etiology
  • Nerve Degeneration / genetics
  • Nerve Degeneration / physiopathology
  • Neurons / pathology
  • Neurons / physiology
  • Organ Culture Techniques
  • Unverricht-Lundborg Syndrome / etiology*
  • Unverricht-Lundborg Syndrome / genetics
  • Unverricht-Lundborg Syndrome / physiopathology*

Substances

  • Cstb protein, mouse
  • Cystatins
  • Excitatory Amino Acid Agonists
  • Cystatin B
  • Kainic Acid