{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:20:56Z","timestamp":1789978856539,"version":"4.0.1"},"reference-count":50,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,10,11]],"date-time":"2018-10-11T00:00:00Z","timestamp":1539216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Dravet syndrome is a rare neurodevelopmental disease, characterized by general cognitive impairment and severe refractory seizures. The majority of patients carry the gene mutation\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">SCN<\/jats:styled-content>\n                        1A\n                      <\/jats:italic>\n                      , leading to a defective sodium channel that contributes to pathogenic brain excitability. A \u03b3\u2010aminobutyric acid (GABAergic) impairment, as in other neurodevelopmental diseases, has been proposed as an additional mechanism, suggesting that seizures could be alleviated by\n                      <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>\n                      ergic therapies. However, up to now the physiological mechanisms underlying the\n                      <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>\n                      ergic dysfunction in Dravet syndrome are still unknown due to the scarce availability of this brain tissue. Here we studied, for the first time, human\n                      <jats:styled-content style=\"fixed-case\">\n                        GABA\n                        <jats:sub>A<\/jats:sub>\n                      <\/jats:styled-content>\n                      \u2010evoked currents using cortical brain tissue from Dravet syndrome patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We transplanted in\n                      <jats:italic>Xenopus<\/jats:italic>\n                      oocytes cell membranes obtained from brain tissues of autopsies of Dravet syndrome patients, tuberous sclerosis complex patients as a pathological comparison, and age\u2010matched controls. Additionally, experiments were performed on oocytes expressing human \u03b11\u03b22\u03b32 and \u03b11\u03b22\n                      <jats:styled-content style=\"fixed-case\">\n                        GABA\n                        <jats:sub>A<\/jats:sub>\n                      <\/jats:styled-content>\n                      receptors.\n                      <jats:styled-content style=\"fixed-case\">\n                        GABA\n                        <jats:sub>A<\/jats:sub>\n                      <\/jats:styled-content>\n                      currents were recorded using the two\u2010microelectrodes voltage\u2010clamp technique. Quantitative real\u2010time polymerase chain reaction, immunohistochemistry, and double\u2010labeling techniques were carried out on the same tissue samples.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found (1) a decrease in\n                      <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>\n                      sensitivity in Dravet syndrome compared to controls, which was related to an increase in \u03b14\u2010 relative to \u03b11\u2010containing\n                      <jats:styled-content style=\"fixed-case\">\n                        GABA\n                        <jats:sub>A<\/jats:sub>\n                      <\/jats:styled-content>\n                      receptors; (2) a shift of the\n                      <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>\n                      reversal potential toward more depolarizing values in Dravet syndrome, and a parallel increase of the chloride transporters\n                      <jats:styled-content style=\"fixed-case\">NKCC<\/jats:styled-content>\n                      1\/\n                      <jats:styled-content style=\"fixed-case\">KCC<\/jats:styled-content>\n                      2 expression ratio; (3) an increase of\n                      <jats:styled-content style=\"fixed-case\">\n                        GABA\n                        <jats:sub>A<\/jats:sub>\n                      <\/jats:styled-content>\n                      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 \u03b3\u2010less\n                      <jats:styled-content style=\"fixed-case\">\n                        GABA\n                        <jats:sub>A<\/jats:sub>\n                      <\/jats:styled-content>\n                      receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      Our study indicates that a dysfunction of the\n                      <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>\n                      ergic 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\n                      <jats:styled-content style=\"fixed-case\">\n                        GABA\n                        <jats:sub>A<\/jats:sub>\n                      <\/jats:styled-content>\n                      receptors could be a target for new therapies.\n                    <\/jats:p>\n                  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