{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:21:16Z","timestamp":1787016076351,"version":"build-2736575974"},"reference-count":60,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,3]]},"abstract":"\n Abstract<\/jats:title>\n \n Heteromeric nicotinic acetylcholine nAChRs (nAChRs) containing the \u03b14 and \u03b22\u00a0subunits (\u03b14\u03b22\n *<\/jats:sup>\n nAChRs) modulate neurotransmitter release in several regions of the brain. In temporal lobe epilepsy, inhibitory GABAergic neurotransmission is altered, whereas no evidence of nicotinic dysfunction has been reported. Here, we investigated, in human epileptic cortical tissues, the ability of \u03b14\u03b22\n *<\/jats:sup>\n nAChRs to modulate synaptic transmission. An increased expression of \u03b14 and \u03b22\u00a0subunits was observed in the temporal cortex of epileptic patients. We then recorded excitatory and inhibitory postsynaptic currents from layer 5 pyramidal neurons in the cortex of temporal lobe epilepsy patients, before and during selective modulation of \u03b14\u03b22\n *<\/jats:sup>\n nAChRs by desformylflustrabromine (a selective \u03b14\u03b22\n *<\/jats:sup>\n positive allosteric modulator). We observed a decrease in both frequency and amplitude of spontaneous excitatory postsynaptic currents, along with an increase in spontaneous inhibitory postsynaptic current frequency. Both these effects were blocked by dihydro\u2010\u03b2\u2010erythroidine, a selective \u03b14* antagonist. \u03b14\u03b22\n *<\/jats:sup>\n activation enhanced the excitability of interneurons (but not of layer 5 pyramidal neurons) by lowering the action potential threshold. Moreover, upon block of action potential propagation by TTX, \u03b14\u03b22\n *<\/jats:sup>\n activation did not alter miniature inhibitory postsynaptic currents recorded from pyramidal neurons, at the same time as reducing the release at glutamatergic synapses by a GABA\n B<\/jats:sub>\n \u2010dependent process.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Heteromeric nicotinic acetylcholine receptors containing the \u03b14 and \u03b22\u00a0subunits (\u03b14\u03b22\n *<\/jats:sup>\n nAChRs) increase GABA release in several regions of the brain.\n <\/jats:p>\n <\/jats:list-item>\n \n \n We observe an increase of \u03b14\u03b22\n *<\/jats:sup>\n nAChRs expression in the temporal cortex of patients with temporal lobe epilepsy (TLE, the most represented human focal epilepsy).\n <\/jats:p>\n <\/jats:list-item>\n \n \n When selectively activated with the positive allosteric modulator desformylflustrabromine (dFBr), \u03b14\u03b22\n *<\/jats:sup>\n nAChRs increase the frequency of GABA release and decrease the glutamate release onto pyramidal neurons in the layer 5 of human TLE cortex.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The increase of GABA release is related to an \u03b14\u03b22\n *<\/jats:sup>\n \u2010mediated enhanced excitability of cortical interneurons; instead, the decrease of glutamate release involves a presynaptic GABA\n B<\/jats:sub>\n \u2010mediated mechanism, being abolished by a selective GABA\n B<\/jats:sub>\n blocker.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Our findings show that the activation of \u03b14\u03b22\n *<\/jats:sup>\n nAChRs induce an increase of the inhibitory tone in human TLE cortex and candidate nicotinic positive allosteric modulators as new pharmacological tools to treat TLE.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp285689","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T17:13:24Z","timestamp":1741713204000},"page":"1645-1662","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["\u03b14\u03b22\n *<\/sup>\n nicotinic acetylcholine receptors drive human temporal glutamate\/GABA balance toward inhibition"],"prefix":"10.1113","volume":"603","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0423-5689","authenticated-orcid":false,"given":"Katiuscia","family":"Martinello","sequence":"first","affiliation":[{"name":"Department of Human, Social & Health Sciences University of Cassino and Southern Lazio Cassino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Addolorata","family":"Mascia","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed Pozzilli 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Gotti","sequence":"additional","affiliation":[{"name":"CNR Institute of Neuroscience Vedano al Lambro Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0698-1148","authenticated-orcid":false,"given":"Sergio","family":"Fucile","sequence":"additional","affiliation":[{"name":"IRCCS Neuromed Pozzilli Italy"},{"name":"Department of Physiology and Pharmacology Sapienza University of Rome Rome 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