A pathogenetic hypothesis of Unverricht–Lundborg disease onset and progression

Franceschetti, Silvana; Sancini, Giulio; Buzzi, A.; Zucchini, Silvia; Paradiso, Beatrice; Magnaghi, Giuseppina; Frassoni, Carolina; Chikhladze, Maia; Avanzini, G.; Simonato, Michele

doi:10.1016/j.nbd.2006.11.006

Cited by 38 publications

(37 citation statements)

References 36 publications

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“…The degree of cell damage was quantified blinded by two investigators, based on two distinct approaches. The first was a modification of a previously described scoring system named "neurodegeneration score" Franceschetti et al, 2007). The score range spanned from 0 (absence of FJB-or silver impregnation-positive neurons) to 5 (maximal neurodegeneration pattern in the hippocampus).…”

Section: Methodsmentioning

confidence: 99%

FGF-2 Overexpression Increases Excitability and Seizure Susceptibility but Decreases Seizure-Induced Cell Loss

Zucchini¹,

Buzzi²,

Barbieri³

et al. 2008

J. Neurosci.

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Fibroblast growth factor 2 (FGF-2) has multiple, pleiotropic effects on the nervous system that include neurogenesis, neuroprotection and neuroplasticity. Thus, alteration in FGF-2 expression patterns may have a profound impact in brain function, both in normal physiology and in pathology. Here, we used FGF-2 transgenic mice (TgFGF2) to study the effects of endogenous FGF-2 overexpression on susceptibility to seizures and to the pathological consequences of seizures. TgFGF2 mice display increased FGF-2 expression in hippocampal pyramidal neurons and dentate granule cells. Increased density of glutamatergic synaptic vesicles was observed in the hippocampus of TgFGF2 mice, and electrophysiological data (input/output curves and patch-clamp recordings in CA1) confirmed an increase in excitatory inputs in CA1, suggesting the presence of a latent hyperexcitability. Indeed, TgFGF2 mice displayed increased susceptibility to kainate-induced seizures compared with wild-type (WT) littermates, in that latency to generalized seizure onset was reduced, whereas behavioral seizure scores and lethality were increased. Finally, WT and TgFGF2 mice with similar seizure scores were used for examining seizure-induced cellular consequences. Neurogenesis and mossy fiber sprouting were not significantly different between the two groups. In contrast, cell damage (assessed with Fluoro-Jade B, silver impregnation and anti-caspase 3 immunohistochemistry) was significantly lower in TgFGF2 mice, especially in the areas of overexpression (CA1 and CA3), indicating reduction of seizure-induced necrosis and apoptosis. These data suggest that FGF-2 may be implicated in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring ictogenesis but reducing seizure-induced cell death.

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Section: Methodsmentioning

confidence: 99%

FGF-2 Overexpression Increases Excitability and Seizure Susceptibility but Decreases Seizure-Induced Cell Loss

Zucchini¹,

Buzzi²,

Barbieri³

et al. 2008

J. Neurosci.

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“…In fact, both transcranial magnetic stimulation protocols [41, 42] on patients, and experiments performed on the EPM1 mouse model indicated reduced intracortical GABA-mediated inhibition and loss of GABA-interneurons [43, 44]. However, other data, obtained in a large group of EPM1 patients, conversely support an increased GABA inhibition, possibly deriving from a compensatory mechanism to counteract hyperexcitability [45].…”

Section: Discussionmentioning

confidence: 99%

The network sustaining action myoclonus: a MEG-EMG study in patients with EPM1

Franceschetti¹,

Canafoglia²,

Rotondi

et al. 2016

BMC Neurol

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BackgroundTo explore the cortical network sustaining action myoclonus and to found markers of the resulting functional impairment, we evaluated the distribution of the cortico-muscular coherence (CMC) and the frequency of coherent cortical oscillations with magnetoencephalography (MEG). All patients had EPM1 (Unverricht-Lundborg) disease known to present with prominent and disabling movement-activated myoclonus.MethodsUsing autoregressive models, we evaluated CMC on MEG sensors grouped in regions of interests (ROIs) above the main cortical areas. The movement was a repeated sustained isometric extension of the right hand and right foot. We compared the data obtained in 10 EPM1 patients with those obtained in 10 age-matched controls.ResultsAs expected, CMC in beta band was significantly higher in EPM1 patients compared to controls in the ROIs exploring the sensorimotor cortex, but, it was also significantly higher in adjacent ROIs ipsilateral and contralateral to the activated limb. Moreover, the beta-CMC peak occurred at frequencies significantly slower and more stable frequencies in EPM1 patients with respect to controls. The frequency of the beta-CMC peak inversely correlated with the severity of myoclonus.Conclusionsthe high and spatially extended beta-CMC peaking in a restricted range of low-beta frequencies in EPM1 patients, suggest that action myoclonus may result not only from an enhanced local synchronization but also from a specific oscillatory activity involving an expanded neuronal pool. The significant relationship between beta-CMC peak frequency and the severity of the motor impairment can represent a useful neurophysiological marker for the patients’ evaluation and follow-up.

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“…It is due to an inherited mutation of the cystatin B gene; cystatin B may have a protective effect in the brain, preventing neurons from dying due to excitotoxicity [48]. This mutation also decreases the number of inhibitory neurons, contributing to the progressive nature of the disease [48]. Some groups have reported that SUDEP occurs in approximately 30% of the patients with Unverricht-Lundborg disease.…”

Section: Genetic Factorsmentioning

confidence: 99%