{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T18:17:39Z","timestamp":1774462659239,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002261","name":"Russian Foundation for Basic Research","doi-asserted-by":"publisher","award":["19-315-60016"],"award-info":[{"award-number":["19-315-60016"]}],"id":[{"id":"10.13039\/501100002261","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Low-frequency electrical stimulation is used to treat some drug-resistant forms of epilepsy. Despite the effectiveness of the method in suppressing seizures, there is a considerable risk of side effects. An optogenetic approach allows the targeting of specific populations of neurons, which can increase the effectiveness and safety of low-frequency stimulation. In our study, we tested the efficacy of the suppression of ictal activity in entorhinal cortex slices in a 4-aminopyridine model with three variants of low-frequency light stimulation (LFLS): (1) activation of excitatory and inhibitory neurons (on Thy1-ChR2-YFP mice), (2) activation of inhibitory interneurons only (on PV-Cre mice after virus injection with channelrhodopsin2 gene), and (3) hyperpolarization of excitatory neurons (on Wistar rats after virus injection with archaerhodopsin gene). Only in the first variant did simultaneous LFLS of excitatory and inhibitory neurons replace ictal activity with interictal activity. We suggest that LFLS caused changes in the concentration gradients of K+ and Na+ cations across the neuron membrane, which activated Na-K pumping. According to the mathematical modeling, the increase in Na-K pump activity in neurons induced by LFLS led to an antiepileptic effect. Thus, a less specific and generalized optogenetic effect on entorhinal cortex neurons was more effective in suppressing ictal activity in the 4-aminopyridine model.<\/jats:p>","DOI":"10.3390\/ijms24010195","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T02:09:03Z","timestamp":1671761343000},"page":"195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Optogenetic Low-Frequency Stimulation of Principal Neurons, but Not Parvalbumin-Positive Interneurons, Prevents Generation of Ictal Discharges in Rodent Entorhinal Cortex in an In Vitro 4-Aminopyridine Model"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9518-5022","authenticated-orcid":false,"given":"Elena Y.","family":"Proskurina","sequence":"first","affiliation":[{"name":"Almazov National Medical Research Centre, 2 Akkuratova Street, 197341 St. Petersburg, Russia"},{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Toreza Prospekt, 194223 St. Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7993-6770","authenticated-orcid":false,"given":"Anton V.","family":"Chizhov","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Toreza Prospekt, 194223 St. Petersburg, Russia"},{"name":"Computational Physics Laboratory, Ioffe Institute, 26 Polytekhnicheskaya Street, 194021 St. Petersburg, Russia"},{"name":"MathNeuro Team, Inria Centre at Universite Cote d\u2019Azur, 06902 Sophia Antipolis, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4503-0647","authenticated-orcid":false,"given":"Aleksey V.","family":"Zaitsev","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Toreza Prospekt, 194223 St. Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.parkreldis.2006.03.001","article-title":"Deep brain stimulation in neurologic disorders","volume":"13","author":"Halpern","year":"2007","journal-title":"Park. Relat. Disord."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"659","DOI":"10.5498\/wjp.v11.i9.659","article-title":"Deep brain stimulation for obsessive-compulsive disorder: A systematic review of worldwide experience after 20 years","volume":"11","author":"Real","year":"2021","journal-title":"World J. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/mds.20341","article-title":"Bilateral subthalamic nucleus deep brain stimulation in a patient with cervical dystonia and essential tremor","volume":"20","author":"Chou","year":"2005","journal-title":"Mov. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.2147\/NDT.S139368","article-title":"Deep brain stimulation in Tourette\u2019s syndrome: Evidence to date","volume":"15","author":"Casagrande","year":"2019","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1528-1167.2011.03348.x","article-title":"Low frequency stimulation of ventral hippocampal commissures reduces seizures in a rat model of chronic temporal lobe epilepsy","volume":"53","author":"Rashid","year":"2012","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ebiom.2016.11.027","article-title":"Entorhinal Principal Neurons Mediate Brain-stimulation Treatments for Epilepsy","volume":"14","author":"Xu","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5765","DOI":"10.1113\/jphysiol.2013.253757","article-title":"Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation","volume":"591","author":"Toprani","year":"2013","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9308","DOI":"10.1523\/JNEUROSCI.17-23-09308.1997","article-title":"CA3-Driven Hippocampal-Entorhinal Loop Controls Rather than Sustains In Vitro Limbic Seizures","volume":"17","author":"Barbarosie","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1152\/jn.00248.2015","article-title":"Blockade of in vitro ictogenesis by low-frequency stimulation coincides with increased epileptiform response latency","volume":"114","author":"Kano","year":"2015","journal-title":"J. Neurophysiol."},{"key":"ref_10","unstructured":"FDA (2022, November 05). Premarket Approval (PMA) Database. Medtronic DBS System for Epilepsy, Available online: https:\/\/www.accessdata.fda.gov\/scripts\/cdrh\/cfdocs\/cfpma\/pma.cfm?id=P960009."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrneurol.2014.59","article-title":"Electrical brain stimulation for epilepsy","volume":"10","author":"Fisher","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/epi.13964","article-title":"Deep brain stimulation for drug-resistant epilepsy","volume":"59","author":"Li","year":"2018","journal-title":"Epilepsia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1212\/WNL.0000000000001334","article-title":"Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy","volume":"84","author":"Salanova","year":"2015","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1111\/j.1528-1167.2010.02536.x","article-title":"Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy","volume":"51","author":"Fisher","year":"2010","journal-title":"Epilepsia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1523\/JNEUROSCI.4352-03.2004","article-title":"Material-Specific Recognition Memory Deficits Elicited by Unilateral Hippocampal Electrical Stimulation","volume":"24","author":"Coleshill","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1038\/nn1525","article-title":"Millisecond-timescale, genetically targeted optical control of neural activity","volume":"8","author":"Boyden","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.expneurol.2015.04.001","article-title":"Seizure reduction through interneuron-mediated entrainment using low frequency optical stimulation","volume":"269","author":"Ladas","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1523\/JNEUROSCI.2244-16.2017","article-title":"Optogenetic Low-Frequency Stimulation of Specific Neuronal Populations Abates Ictogenesis","volume":"37","author":"Shiri","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.bbrc.2021.10.002","article-title":"Photostimulation activates fast-spiking interneurons and pyramidal cells in the entorhinal cortex of Thy1-ChR2-YFP line 18 mice","volume":"580","author":"Proskurina","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1016\/j.brs.2020.07.013","article-title":"Presynaptic GABAB receptors underlie the antiepileptic effect of low-frequency electrical stimulation in the 4-aminopyridine model of epilepsy in brain slices of young rats","volume":"13","author":"Smirnova","year":"2020","journal-title":"Brain Stimul."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chizhov, A.V., Zefirov, A.V., Amakhin, D.V., Smirnova, E.Y., and Zaitsev, A.V. (2018). Minimal model of interictal and ictal discharges \u201cEpileptor-2\u201d. PLoS Comput. Biol., 14.","DOI":"10.1371\/journal.pcbi.1006186"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1152\/jn.00841.2014","article-title":"Selective activation of parvalbumin- or somatostatin-expressing interneurons triggers epileptic seizurelike activity in mouse medial entorhinal cortex","volume":"113","author":"Yekhlef","year":"2015","journal-title":"J. Neurophysiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1255263","DOI":"10.1126\/science.1255263","article-title":"Fast-spiking, parvalbumin+ GABAergic interneurons: From cellular design to microcircuit function","volume":"345","author":"Hu","year":"2014","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/bs.pbr.2016.04.012","article-title":"Involvement of cortical fast-spiking parvalbumin-positive basket cells in epilepsy","volume":"226","author":"Jiang","year":"2016","journal-title":"Prog. Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1152\/jn.90396.2008","article-title":"Parvalbumin-Positive Basket Interneurons in Monkey and Rat Prefrontal Cortex","volume":"100","author":"Povysheva","year":"2008","journal-title":"J. Neurophysiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/0168-0102(95)01008-4","article-title":"The distribution of two calcium binding proteins, calbindin D-28K and parvalbumin, in the entorhinal cortex of the adult mouse","volume":"24","author":"Fujimaru","year":"1996","journal-title":"Neurosci. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"107751","DOI":"10.1016\/j.neuropharm.2019.107751","article-title":"Optogenetic and chemogenetic therapies for epilepsy","volume":"168","author":"Walker","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1177\/1073858418805002","article-title":"GABAergic Interneurons in Seizures: Investigating Causality with Optogenetics","volume":"25","author":"Magloire","year":"2019","journal-title":"Neuroscientist"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"a022764","DOI":"10.1101\/cshperspect.a022764","article-title":"GABAergic Synchronization in Epilepsy","volume":"6","author":"Khazipov","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chizhov, A.V., Amakhin, D.V., and Zaitsev, A.V. (2019). Mathematical model of Na-K-Cl homeostasis in ictal and interictal discharges. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0213904"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"011924","DOI":"10.1103\/PhysRevE.75.011924","article-title":"Population model of hippocampal pyramidal neurons, linking a refractory density approach to conductance-based neurons","volume":"75","author":"Chizhov","year":"2007","journal-title":"Phys. Rev. E"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00422-017-0727-9","article-title":"Conductance-based refractory density approach: Comparison with experimental data and generalization to lognormal distribution of input current","volume":"111","author":"Chizhov","year":"2017","journal-title":"Biol. Cybern."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.bbrc.2018.12.070","article-title":"Spatial propagation of interictal discharges along the cortex","volume":"508","author":"Chizhov","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chizhov, A.V., Amakhin, D.V., and Zaitsev, A.V. (2017). Computational model of interictal discharges triggered by interneurons. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185752"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.eplepsyres.2018.04.005","article-title":"Potassium dynamics and seizures: Why is potassium ictogenic?","volume":"143","author":"Uva","year":"2018","journal-title":"Epilepsy Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1134\/S0022093021020058","article-title":"Age-Dependent Generation of Epileptiform Activity in the 4-Aminopyridine Model with Slices of the Rat Entorhinal Cortex","volume":"57","author":"Smirnova","year":"2021","journal-title":"J. Evol. Biochem. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chizhov, A.V., Amakhin, D.V., Smirnova, E.Y., and Zaitsev, A.V. (2022). Ictal wavefront propagation in slices and simulations with conductance-based refractory density model. PLOS Comput. Biol., 18.","DOI":"10.1371\/journal.pcbi.1009782"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3356","DOI":"10.1152\/jn.00460.2014","article-title":"Electrogenic properties of the Na+\/K+ ATPase control transitions between normal and pathological brain states","volume":"113","author":"Krishnan","year":"2015","journal-title":"J. Neurophysiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e68541","DOI":"10.7554\/eLife.68541","article-title":"Focal seizures are organized by feedback between neural activity and ion concentration changes","volume":"11","author":"Gentiletti","year":"2022","journal-title":"eLife"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1152\/jn.00541.2013","article-title":"Oxygen and seizure dynamics: II. Computational modeling","volume":"112","author":"Wei","year":"2014","journal-title":"J. Neurophysiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.neuroscience.2018.02.044","article-title":"Na+, K+-ATPase Activating Antibody Displays in vitro and in vivo Beneficial Effects in the Pilocarpine Model of Epilepsy","volume":"377","author":"Mello","year":"2018","journal-title":"Neuroscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.neuroscience.2015.04.031","article-title":"Contrasting effects of Na+, K+-ATPase activation on seizure activity in acute versus chronic models","volume":"298","author":"Funck","year":"2015","journal-title":"Neuroscience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1097\/WNP.0b013e3181fe0709","article-title":"Interictal spikes precede ictal discharges in an organotypic hippocampal slice culture model of epileptogenesis","volume":"27","author":"Berdichevsky","year":"2010","journal-title":"J. Clin. Neurophysiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1134\/S0022093022050015","article-title":"Regulation of Potassium and Chloride Concentrations in Nervous Tissue as a Method of Anticonvulsant Therapy","volume":"58","author":"Proskurina","year":"2022","journal-title":"J. Evol. Biochem. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e19322","DOI":"10.7554\/eLife.19322","article-title":"Na(+)\/K(+) pump interacts with the h-current to control bursting activity in central pattern generator neurons of leeches","volume":"5","author":"Kueh","year":"2016","journal-title":"eLife"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0076-6879(92)07008-C","article-title":"Correction for liquid junction potentials in patch clamp experiments","volume":"Volume 207","author":"Neher","year":"1992","journal-title":"Methods in Enzymology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:48:36Z","timestamp":1760147316000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,22]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24010195"],"URL":"https:\/\/doi.org\/10.3390\/ijms24010195","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,22]]}}}