Loss of cortical GABA terminals in Unverricht–Lundborg disease

Buzzi, A.; Chikhladze, Maia; Falcicchia, Chiara; Paradiso, Beatrice; Lanza, Giovanni; Soukupová, Marie; Marti, Matteo; Morari, Michele; Franceschetti, Silvana; Simonato, Michele

doi:10.1016/j.nbd.2012.04.005

Cited by 36 publications

(55 citation statements)

References 40 publications

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“…Various neurophysiological findings have shown that cortical myoclonus is related to excess EEG oscillations closely coupled with EMG bursts corresponding to the jerks (Panzica et al 2003). The mechanisms responsible for neuronal synchronisation are still unclear, but evidence obtained by means of transcranial magnetic stimulation protocols indicate a prominent impairment of intracortical inhibition (Manganotti et al 2001;Canafoglia et al 2010), a defect that is in line with data obtained in the mouse model of the disease that suggest decreased GABAmediated inhibition (Buzzi et al 2012).…”

Section: Discussionsupporting

confidence: 68%

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study

et al. 2014

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Multimodal human brain mapping has been proposed as an integrated approach capable of improving the recognition of the cortical correlates of specific neurological functions. We used simultaneous EEG-fMRI (functional magnetic resonance imaging) and EEG-TDfNIRS (time domain functional near-infrared spectroscopy) recordings to compare different hemodynamic methods with changes in EEG in ten patients with progressive myoclonic epilepsy and 12 healthy controls. We evaluated O 2 Hb, HHb and Blood oxygen level-dependent (BOLD) changes and event-related desynchronization/synchronization (ERD/ERS) in the a and b bands of all of the subjects while they performed a simple motor task. The general linear model was used to obtain comparable fMRI and TDfNIRS activation maps. We also analyzed cortical thickness in order to evaluate any structural changes. In the patients, the TD-NIRS and fMRI data significantly correlated and showed a significant lessening of the increase in O 2 Hb and the decrease in BOLD. The post-movement b rebound was minimal or absent in patients. Cortical thickness was moderately reduced in the motor area of the patients and correlated with the reduction in the hemodynamic signals. The fMRI and TD-NIRS results were consistent, significantly correlated and showed smaller hemodynamic changes in the patients. This finding may be partially attributable to mild cortical thickening. However, cortical hyperexcitability, which is known to generate myoclonic jerks and probably accounts for the lack of EEG b-ERS, did not reflect any increased energy requirement. We hypothesize that this is due to a loss of inhibitory neuronal components that typically fire at high frequencies.

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Section: Discussionsupporting

confidence: 68%

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study

et al. 2014

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“…A decrease in the number of GABAergic terminals leading to reduced GABA inhibition has previously been reported in cerebral cortex of aged Cstb −/− mice [47]. The loss of interneurons in aged mice can further reduce the GABA inhibition (our unpublished observation and [47]).…”

Section: Discussionsupporting

confidence: 67%

“…The loss of interneurons in aged mice can further reduce the GABA inhibition (our unpublished observation and [47]). Consistent with the mouse data, a loss of pre-synaptic GABAergic marker VGAT was also detected in the brain of a fully symptomatic EPM1 patient [47].…”

Section: Discussionmentioning

confidence: 73%

Gene Expression Alterations in the Cerebellum and Granule Neurons of Cstb−/− Mouse Are Associated with Early Synaptic Changes and Inflammation

et al. 2014

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Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited neurodegenerative disease, manifesting with myoclonus, seizures and ataxia, caused by mutations in the cystatin B (CSTB) gene. With the aim of understanding the molecular basis of pathogenetic events in EPM1 we characterized gene expression changes in the cerebella of pre-symptomatic postnatal day 7 (P7) and symptomatic P30 cystatin B -deficient (Cstb−/−) mice, a model for the disease, and in cultured Cstb−/− cerebellar granule cells using a pathway-based approach. Differentially expressed genes in P7 cerebella were connected to synaptic function and plasticity, and in cultured cerebellar granule cells, to cell cycle, cytoskeleton, and intracellular transport. In particular, the gene expression data pinpointed alterations in GABAergic pathway. Electrophysiological recordings from Cstb−/− cerebellar Purkinje cells revealed a shift of the balance towards decreased inhibition, yet the amount of inhibitory interneurons was not declined in young animals. Instead, we found diminished number of GABAergic terminals and reduced ligand binding to GABAA receptors in Cstb−/− cerebellum. These results suggest that alterations in GABAergic signaling could result in reduced inhibition in Cstb−/− cerebellum leading to the hyperexcitable phenotype of Cstb−/− mice. At P30, the microarray data revealed a marked upregulation of immune and defense response genes, compatible with the previously reported early glial activation that precedes neuronal degeneration. This further implies the role of early-onset neuroinflammation in the pathogenesis of EPM1.

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“…In a case report of Unverricht-Lundborg disease, the most common progressive myoclonic epilepsy, VGAT-IR was decreased in the cortex of the examined patient (Buzzi et al, 2012). In the resected cortex from pediatric epilepsy surgery patients with type II cortical dysplasia GAD-labeled neurons displayed larger somata and VGAT and GABA transporter 1 staining showed a dense plexus surrounding cytomegalic neurons (Andre et al, 2010).…”

Section: Slc32 Familymentioning

confidence: 96%

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Liefferinge¹,

Massie²,

Portelli³

et al. 2013

Front. Cell. Neurosci.

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The vesicular neurotransmitter transporters (VNTs) are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

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Loss of cortical GABA terminals in Unverricht–Lundborg disease

Cited by 36 publications

References 40 publications

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study

Gene Expression Alterations in the Cerebellum and Granule Neurons of Cstb−/− Mouse Are Associated with Early Synaptic Changes and Inflammation

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

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