UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

A novel GABAergic dysfunction in human Dravet syndrome

Ruffolo, G; Cifelli, P; Roseti, C; Thom, M; Van Vliet, EA; Limatola, C; Aronica, E; (2018) A novel GABAergic dysfunction in human Dravet syndrome. Epilepsia , 59 (11) pp. 2106-2117. 10.1111/epi.14574.

[img] Text (Article)
Thom_Ruffolo et al. EPILEPSIA revisedfinal.pdf - ["content_typename_Accepted version" not defined]
Access restricted to UCL open access staff until 12 October 2019.

Download (742kB)
[img] Text (Supporting Information)
Thom_Supporting informationREVISED.pdf - ["content_typename_Accepted version" not defined]
Access restricted to UCL open access staff until 12 October 2019.

Download (448kB)

Abstract

OBJECTIVE: Dravet syndrome is a rare neurodevelopmental disease, characterized by general cognitive impairment and severe refractory seizures. The majority of patients carry the gene mutation SCN1A, leading to a defective sodium channel that contributes to pathogenic brain excitability. A γ-aminobutyric acid (GABAergic) impairment, as in other neurodevelopmental diseases, has been proposed as an additional mechanism, suggesting that seizures could be alleviated by GABAergic therapies. However, up to now the physiological mechanisms underlying the GABAergic dysfunction in Dravet syndrome are still unknown due to the scarce availability of this brain tissue. Here we studied, for the first time, human GABAA -evoked currents using cortical brain tissue from Dravet syndrome patients. METHODS: We transplanted in Xenopus oocytes cell membranes obtained from brain tissues of autopsies of Dravet syndrome patients, tuberous sclerosis complex patients as a pathological comparison, and age-matched controls. Additionally, experiments were performed on oocytes expressing human α1β2γ2 and α1β2 GABAA receptors. GABAA currents were recorded using the two-microelectrodes voltage-clamp technique. Quantitative real-time polymerase chain reaction, immunohistochemistry, and double-labeling techniques were carried out on the same tissue samples. RESULTS: We found (1) a decrease in GABA sensitivity in Dravet syndrome compared to controls, which was related to an increase in α4- relative to α1-containing GABAA receptors; (2) a shift of the GABA reversal potential toward more depolarizing values in Dravet syndrome, and a parallel increase of the chloride transporters NKCC1/KCC2 expression ratio; (3) an increase of GABAA currents induced by low doses of cannabidiol both in Dravet syndrome and tuberous sclerosis complex comparable to that induced by a classical benzodiazepine, flunitrazepam, that still persists in γ-less GABAA receptors. SIGNIFICANCE: Our study indicates that a dysfunction of the GABAergic system, considered as a feature of brain immaturity, together with defective sodium channels, can contribute to a general reduction of inhibitory efficacy in Dravet brain, suggesting that GABAA receptors could be a target for new therapies.

Type: Article
Title: A novel GABAergic dysfunction in human Dravet syndrome
Location: United States
DOI: 10.1111/epi.14574
Publisher version: https://doi.org/10.1111/epi.14574
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: GABAA receptor, GABAA reversal potential, cannabidiol, epilepsy, human brain tissue
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: http://discovery.ucl.ac.uk/id/eprint/10061107
Downloads since deposit
0Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item