Unverricht-Lundborg disease (ULD) is the most common
progressive myoclonic epilepsy. Its etiology has been identified in a defect of a
protease inhibitor,
cystatin B (CSTB), but the mechanism(s) by which this defect translates in the clinical manifestations of the disease are still obscure. We tested the hypothesis that ULD is accompanied by a loss of cortical
GABA inhibition in a murine model (the CSTB knockout mouse) and in a human case. Cortical
GABA signaling has been investigated measuring VGAT immunohistochemistry (a histological marker of the density of
GABA terminals),
GABA release from synaptosomes and paired-pulse stimulation. In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of
GABA interneurons. A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient. This implicates a reduction in
GABA synaptic transmission, which was confirmed in the mouse model as reduction in
GABA release from isolated nerve terminals and as loss of electrophysiologically measured
GABA inhibition. The alterations in VGAT immunolabeling progressed in time, paralleling the worsening of
myoclonus. These results provide direct evidence that loss of cortical
GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors
myoclonus and
seizures. These findings contribute to the understanding of the pathogenic mechanism of ULD and of the neurobiological basis of the effect of currently employed drugs.