{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:52:52Z","timestamp":1786121572715,"version":"build-2736575974"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"<jats:p>Spike-and-wave discharges (SWDs) of absence seizures and slowly oscillating Up-Down states of non-REM sleep and are both manifestations of large-scale synchronized cortical activity, yet the circuit mechanisms differentiating these phenomena remain poorly understood. Cholinergic modulation via nicotinic acetylcholine receptors (nAChRs) plays a key role in shaping cortical excitability. Here, we investigated the role of \u03b15 subunit-containing nAChRs in regulating spontaneous cortical activity and the transition to paroxysmal states. We used acute brain slices from wild type (wt) and \u03b15 knockout (\u03b15KO) mice and performed simultaneous intracellular and extracellular recordings in somatosensory cortical layer II\/III. We found that \u03b15KO networks exhibit a generalized slowing of spontaneous cortical activity reflected in all metrics examined: shorter and less frequent Up states, longer Down states and reduced Entire Spiking Activity (ESA) compared to wt. Spectral analysis revealed complementary changes in the power of Delta, Beta and Alpha bands during Up states, and additional state-dependent power alterations across frequency bands. Upon blockage of phasic GABAa R-mediated inhibition, both wt and \u03b15KO networks displayed increased transitions to active states; however, unlike wt networks, mutants had unaltered ESA signal and a striking tolerance to the typical high-amplitude SWDs. These findings reveal a critical role of \u03b15-nAChRs in regulating cortical excitability and ictogenesis. Given their cell-type specific expression, we hypothesize their action is mediated through a VIP-SST-Pyramidal neuron disinhibitory circuit. Hence, our study provides evidence for a novel cell-type-specific pathway in which \u03b15-mediated nicotinic signaling tightly regulates state transitions in cortical networks. By modulating SST+ activity, \u03b15-nAChRs influence both spontaneous Up-Down states and the emergence of epileptiform discharges.<\/jats:p>","DOI":"10.3389\/fncir.2026.1858893","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T05:28:29Z","timestamp":1786080509000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b15-containing nicotinic acetylcholine receptors regulate state transitions in cortical networks and modulate susceptibility to epileptiform discharges"],"prefix":"10.3389","volume":"20","author":[{"given":"Ani","family":"Kaplanian","sequence":"first","affiliation":[{"name":"Center for Basic Research, Biomedical Research Foundation of Academy of Athens (BRFAA)","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vinos","sequence":"additional","affiliation":[{"name":"Center for Basic Research, Biomedical Research Foundation of Academy of Athens (BRFAA)","place":["Athens, Greece"]},{"name":"Department of History and Philosophy of Science, University of Athens","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Maskos","sequence":"additional","affiliation":[{"name":"Institute Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irini","family":"Skaliora","sequence":"additional","affiliation":[{"name":"Center for Basic Research, Biomedical Research Foundation of Academy of Athens (BRFAA)","place":["Athens, Greece"]},{"name":"Department of History and Philosophy of Science, University of Athens","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"9664","DOI":"10.1523\/JNEUROSCI.23-29-09664.2003","article-title":"Major differences in inhibitory synaptic transmission onto two neocortical interneuron subclasses","volume":"23","author":"Bacci","year":"2003","journal-title":"J. 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Neurosci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/nature08002","article-title":"Driving fast-spiking cells induces gamma rhythm and controls sensory responses","volume":"459","author":"Cardin","year":"2009","journal-title":"Nature"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1016\/S0028-3908(99)00139-2","article-title":"On the putative contribution of GABAB receptors to the electrical events occuring during spontaneous spike and wave discharges","volume":"38","author":"Charpier","year":"1999","journal-title":"Neuropharmacology"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1016\/j.neuron.2017.11.033","article-title":"Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations","volume":"96","author":"Chen","year":"2017","journal-title":"Neuron"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1523\/JNEUROSCI.2624-13.2013","article-title":"Target-specific effects of somatostatin-expressing interneurons on neocortical visual processing","volume":"33","author":"Cottam","year":"2013","journal-title":"J. Neurosci."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1113\/jphysiol.2012.248088","article-title":"Distinct roles of GABAB1a- and GABAB1b-containing GABAB receptors in spontaneous and evoked termination of persistent cortical activity","volume":"591","author":"Craig","year":"2013","journal-title":"J. Physiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"114197","DOI":"10.1016\/j.celrep.2024.114197","article-title":"Feedforward and disinhibitory circuits differentially control activity of cortical somatostatin interneurons during behavioral state transitions","volume":"43","author":"de Brito Van Velze","year":"2024","journal-title":"Cell Rep."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e66960","DOI":"10.7554\/eLife.66960","article-title":"Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex","volume":"10","author":"de Filippo","year":"2021","journal-title":"eLife"},{"key":"ref15","first-page":"1","article-title":"Toward understanding the diverse roles of perisomatic interneurons in epilepsy","volume":"22","author":"Dudok","year":"2021","journal-title":"Eppilepsy Currents."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ceca.2003.08.006","article-title":"Ca2+ permeability of nicotinic acetylcholine receptors","volume":"35","author":"Fucile","year":"2004","journal-title":"Cell Calcium"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.neuron.2020.12.018","article-title":"Cell-type-specific nicotinic input disinhibits mouse barrel cortex during active sensing","volume":"109","author":"Gasselin","year":"2021","journal-title":"Neuron"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1177\/155005941004100404","article-title":"EEG alpha asymmetry in schizophrenia, depression, PTSD, panic disorder, ADHD and conduct disorder","volume":"41","author":"Gordon","year":"2010","journal-title":"Clin. 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Pharmacol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1152\/jn.00263.2005","article-title":"An oscillatory hierarchy controlling neuronal excitability and stimulus processing in the auditory cortex","volume":"94","author":"Lakatos","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1016\/j.celrep.2018.10.029","article-title":"Combined positive and negative feedback allows modulation of neuronal oscillation frequency during sensory processing","volume":"25","author":"Lee","year":"2018","journal-title":"Cell Rep."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"7513","DOI":"10.1523\/JNEUROSCI.6162-08.2009","article-title":"Distinct roles of GABA(A) and GABA(B) receptors in balancing and terminating persistent cortical activity","volume":"29","author":"Mann","year":"2009","journal-title":"J. Neurosci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"108774","DOI":"10.1016\/j.celrep.2021.108774","article-title":"Cell-type-specific recruitment of GABAergic interneurons in the primary somatosensory cortex by long-range inputs","volume":"34","author":"Naskar","year":"2021","journal-title":"Cell Rep."},{"key":"ref32","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3389\/fncir.2016.00052","article-title":"Distinct roles of SOM and VIP interneurons during cortical up states","volume":"10","author":"Neske","year":"2016","journal-title":"Front. Neural Circuits"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1523\/JNEUROSCI.2279-14.2015","article-title":"Contributions of diverse excitatory and inhibitory neurons to recurrent network activity in cerebral cortex","volume":"35","author":"Neske","year":"2015","journal-title":"J. Neurosci."},{"key":"ref34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1113\/JP272022","article-title":"Active subthreshold dendritic conductances shape the local field potential","volume":"594","author":"Ness","year":"2016","journal-title":"J. Physiol."},{"key":"ref35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1523\/JNEUROSCI.2273-06.2006","article-title":"Dissociation between local field potentials and spiking activity in macaque inferior temporal cortex reveals diagnosticity-based encoding of complex objects","volume":"26","author":"Nielsen","year":"2006","journal-title":"J. Neurosci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1093\/schbul\/sby093","article-title":"Genome-wide variants shared between smoking quantity and schizophrenia on 15q25 are associated with CHRNA5 expression in the brain","volume":"45","author":"Ohi","year":"2018","journal-title":"Schizophr. 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Neurosci."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.neuron.2013.05.023","article-title":"A biophysically detailed model of neocortical local field potentials predicts the critical role of active membrane currents","volume":"79","author":"Reimann","year":"2013","journal-title":"Neuron"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.cub.2013.12.004","article-title":"Timing of single-neuron and local field potential responses in the human medial temporal lobe","volume":"24","author":"Rey","year":"2014","journal-title":"Curr. Biol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fnsyn.2018.00043","article-title":"Long-term effects of early life seizures on endogenous local network activity of the mouse neocortex","volume":"10","author":"Rigas","year":"2018","journal-title":"Front. Synaptic Neurosci."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/s13293-017-0143-9","article-title":"Sex differences in endogenous cortical network activity: spontaneously recurring up\/down states","volume":"8","author":"Sigalas","year":"2017","journal-title":"Biol. Sex Differ."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"11196","DOI":"10.1523\/JNEUROSCI.5222-14.2015","article-title":"High-affinity nicotinic receptors modulate spontaneous cortical up states in vitro","volume":"35","author":"Sigalas","year":"2015","journal-title":"J. Neurosci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/nature07991","article-title":"Parvalbumin neurons and gamma rhythms enhance cortical circuit performance","volume":"459","author":"Sohal","year":"2009","journal-title":"Nature"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"RC223","DOI":"10.1523\/JNEUROSCI.22-10-j0003.2002","article-title":"Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons","volume":"22","author":"Stell","year":"2002","journal-title":"J. Neurosci."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/j.0013-9580.2003.12006.x","article-title":"Sleep oscillations developing into seizures in corticothalamic systems","volume":"44","author":"Steriade","year":"2003","journal-title":"Epilepsia"},{"key":"ref48","first-page":"3","article-title":"Spike-wave complexes and fast components of cortically generated seizures. II. Extra- and intracellular patterns","volume":"80","author":"Steriade","year":"1998","journal-title":"J. Neurophysiol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"3252","DOI":"10.1523\/JNEUROSCI.13-08-03252.1993","article-title":"A novel slow (<1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components","volume":"13","author":"Steriade","year":"1993","journal-title":"J. Neurosci."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1152\/jn.2001.85.5.1969","article-title":"Natural waking and sleep states: a view from inside neocortical neurons","volume":"85","author":"Steriade","year":"2001","journal-title":"J. Neurophysiol."},{"key":"ref51","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1460-9568.2007.05413.x","article-title":"Role of GABA A inhibition in modulation of pyramidal tract neuron activity during postural corrections","volume":"25","author":"Tamarova","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref52","doi-asserted-by":"crossref","first-page":"40211","DOI":"10.1038\/srep40211","article-title":"Local field potentials primarily reflect inhibitory neuron activity in human and monkey cortex","volume":"4","author":"Tele\u0144czuk","year":"2017","journal-title":"Sci. Rep."},{"key":"ref8001","article-title":"MATLAB version: 9.7 (R2019b), Natick, Massachusetts: The MathWorks Inc.","year":"2019"},{"key":"ref53","first-page":"13","article-title":"Neocortical layer 6, a review","volume":"4","author":"Thomson","year":"2010","journal-title":"Front. Neuroanat."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/S0306-4522(02)00300-7","article-title":"The role of chloride-dependent inhibition and the activity of fast-spiking neurons during cortical spike\u2013wave electrographic seizures","volume":"114","author":"Timofeev","year":"2002","journal-title":"Neuroscience"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1152\/jn.00523.2003","article-title":"Contribution of intrinsic neuronal factors in the generation of cortically driven electrographic seizures","volume":"92","author":"Timofeev","year":"2004","journal-title":"J. Neurophysiol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.neuroscience.2003.08.051","article-title":"Neocortical seizures: initiation, development and cessation","volume":"123","author":"Timofeev","year":"2004","journal-title":"Neuroscience"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41598-017-03269-9","article-title":"High-throughput analysis of in-vitro LFP electrophysiological signals: a validated workflow\/software package","volume":"7","author":"Tsakanikas","year":"2017","journal-title":"Sci. Rep."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.cub.2015.01.035","article-title":"Neocortical somatostatin neurons reversibly silence excitatory transmission via GABAb receptors","volume":"25","author":"Urban-Ciecko","year":"2015","journal-title":"Curr. Biol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1002\/jnr.25156","article-title":"The role of selective SATB1 deletion in somatostatin expressing interneurons on endogenous network activity and the transition to epilepsy","volume":"101","author":"Vasilopoulos","year":"2023","journal-title":"J. Neurosci. Res."},{"key":"ref61","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0006-8993(90)90248-A","article-title":"The distribution of mRNA encoded by a new member of the neuronal nicotinic acetylcholine receptor gene family (alpha 5) in the rat central nervous system","volume":"526","author":"Wada","year":"1990","journal-title":"Brain Res."},{"key":"ref62","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/cne.20357","article-title":"Expression of alpha5 nicotinic acetylcholine receptor subunit mRNA during hippocampal and cortical development","volume":"481","author":"Winzer-Serhan","year":"2005","journal-title":"J. Comput. Neurosci."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41398-025-03230-9","article-title":"Linking altered neuronal and synaptic properties to nicotinic receptor Alpha5 subunit gene dysfunction: a translational investigation in rat mPFC and human cortical layer 6","volume":"15","author":"Yang","year":"2025","journal-title":"Transl. 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