{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T08:35:38Z","timestamp":1769848538538,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,2]],"date-time":"2024-03-02T00:00:00Z","timestamp":1709337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 Research and Innovation Program","award":["952455"],"award-info":[{"award-number":["952455"]}]},{"name":"EpiEpiNet","award":["952455"],"award-info":[{"award-number":["952455"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>Among the most prevalent neurological disorders, epilepsy affects about 1% of the population worldwide. We previously found, using human epileptic tissues, that GABAergic neurotransmission impairment is a key mechanism that drives the pathological phenomena that ultimately lead to generation and recurrence of seizures. Using both a \u201cmicrotransplantation technique\u201d and synaptosomes preparations from drug-resistant temporal lobe epilepsies (TLEs), we used the technique of two-electrode voltage clamp to record GABA-evoked currents, focusing selectively on the synaptic \u201cfast inhibition\u201d mediated by low-affinity GABAA receptors. Here, we report that the use-dependent GABA current desensitization (i.e., GABA rundown, which is evoked by applying to the cells consecutive pulses of GABA, at high concentration), which is a distinguishing mark of TLE, is mainly dependent on a dysfunction that affects synaptic GABAA receptors. In addition, using the same approaches, we recorded a depolarized GABA reversal potential in synaptosomes samples from the human epileptic subicula of TLE patients. These results, which confirm previous experiments using total membranes, suggest an altered chloride homeostasis in the synaptic area. Finally, the lack of a Zn2+ block of GABA-evoked currents using the synaptosomes supports the enrichment of \u201csynaptic fast inhibitory\u201d GABAA receptors in this preparation. Altogether, our findings suggest a pathophysiological role of low-affinity GABAA receptors at the synapse, especially during the fast and repetitive GABA release underlying recurrent seizures.<\/jats:p>","DOI":"10.3390\/membranes14030064","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T08:03:47Z","timestamp":1709539427000},"page":"64","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Membranes and Synaptosomes Used to Investigate Synaptic GABAergic Currents in Epileptic Patients"],"prefix":"10.3390","volume":"14","author":[{"given":"Alessandro","family":"Gaeta","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4471-2782","authenticated-orcid":false,"given":"Lilian Juliana","family":"Lissner","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Alfano","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Roma, 00166 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierangelo","family":"Cifelli","sequence":"additional","affiliation":[{"name":"Department of Applied Clinical and Biotechnological Sciences, University of L\u2019Aquila, 67100 L\u2019 Aquila, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Morano","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, University of Rome Sapienza, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9863-0371","authenticated-orcid":false,"given":"Cristina","family":"Roseti","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy"},{"name":"Center for Research in Neuroscience, University of Insubria, 21052 Busto Arsizio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-2682","authenticated-orcid":false,"given":"Angela","family":"Di Iacovo","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3542-3770","authenticated-orcid":false,"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Department of (Neuro)Pathology, Amsterdam Neuroscience, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Stichting Epilepsie Instellingen Nederland, 0397 Heemstede, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6026-927X","authenticated-orcid":false,"given":"Eleonora","family":"Palma","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy"},{"name":"IRCCS San Raffaele Roma, 00166 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6554-5496","authenticated-orcid":false,"given":"Gabriele","family":"Ruffolo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy"},{"name":"IRCCS San Raffaele Roma, 00166 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0140-6736(18)32596-0","article-title":"Epilepsy in Adults","volume":"393","author":"Thijs","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"674483","DOI":"10.3389\/fneur.2021.674483","article-title":"The Pharmacoresistant Epilepsy: An Overview on Existant and New Emerging Therapies","volume":"12","author":"Fattorusso","year":"2021","journal-title":"Front. 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