{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:04:24Z","timestamp":1785423864441,"version":"3.56.0"},"posted":{"date-parts":[[2025,7,10]]},"group-title":"Neuroscience","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01 NS092809"],"award-info":[{"award-number":["R01 NS092809"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 NS123933"],"award-info":[{"award-number":["R01 NS123933"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Cerebellar Purkinje cells (PCs) fire spontaneously in the absence of excitatory input and depend heavily on inhibition to modify their firing activity. Previous work in the field has described phasic inhibition arising primarily from molecular layer interneuron\u2013PC (MLI-PC) synapses extensively, however little work explores other sources of inhibition in PCs. Several types of neurons throughout the brain and within the cerebellum receive significant inhibition through tonic currents, a low amplitude current resulting from ambient GABA acting upon extrasynaptic GABA\n                  <jats:sub>A<\/jats:sub>\n                  receptors. Through the use of ex vivo electrophysiology and single cell RNA analysis, we investigated the role of tonic inhibition in PCs. We find that PCs have a significant tonic current mediated by \u03b4-subunit containing GABA\n                  <jats:sub>A<\/jats:sub>\n                  receptors, which accounts for roughly half of the total inhibitory current. We also examined PC tonic GABA currents in DMD\n                  <jats:sup>mdx<\/jats:sup>\n                  mice, a mouse model of Duchenne Muscular Dystrophy with \u223c50% reduction in phasic inhibitory currents. We find that tonic inhibition is dramatically upregulated in DMD\n                  <jats:sup>mdx<\/jats:sup>\n                  PCs, suggesting a possible compensatory mechanism to account for the loss in phasic inhibition. Furthermore, roughly 80% of the total inhibition is derived from tonic currents in this condition. These data suggest that under physiological conditions, PCs are subject to both tonic and phasic inhibition, and that adjustments in the balance of inhibition may be a physiological mechanism for PC function. These data reveal an expanded range of inhibitory currents in PC which may be critical to regulating PC activity in both normal and pathophysiological states.\n                <\/jats:p>","DOI":"10.1101\/2025.07.07.663562","type":"posted-content","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T01:40:41Z","timestamp":1752198041000},"source":"Crossref","is-referenced-by-count":0,"title":["Tonic GABA\n                  <sub>A<\/sub>\n                  receptor currents in Cerebellar Purkinje cells of wild-type and DMD\n                  <sup>mdx<\/sup>\n                  mice"],"prefix":"10.64898","author":[{"given":"Shaarang","family":"Mitra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailesh N.","family":"Khatri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Pugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025071203401198000_2025.07.07.663562v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(03)03018-X"},{"key":"2025071203401198000_2025.07.07.663562v1.2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2002.88.3.1407"},{"key":"2025071203401198000_2025.07.07.663562v1.3","doi-asserted-by":"crossref","unstructured":"Briatore F , Pregno G , Di Angelantonio S , Frola E , De Stefano ME , Vaillend C , Sasso\u00e8-Pognetto M , Patrizi A . Dystroglycan Mediates Clustering of Essential GABAergic Components in Cerebellar Purkinje Cells. Front Mol Neurosci. 2020 Aug 28;13:164.","DOI":"10.3389\/fnmol.2020.00164"},{"key":"2025071203401198000_2025.07.07.663562v1.4","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021806"},{"key":"2025071203401198000_2025.07.07.663562v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.12.012"},{"key":"2025071203401198000_2025.07.07.663562v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3445"},{"key":"2025071203401198000_2025.07.07.663562v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307231101"},{"key":"2025071203401198000_2025.07.07.663562v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nature02442"},{"key":"2025071203401198000_2025.07.07.663562v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/pros.22625"},{"key":"2025071203401198000_2025.07.07.663562v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.430"},{"issue":"1","key":"2025071203401198000_2025.07.07.663562v1.11","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1038\/s41467-019-10800-1","article-title":"Modulation of extrasynaptic GABAA alpha 5 receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a circuit specific manner","volume":"10","year":"2019","journal-title":"Nat Commun"},{"key":"2025071203401198000_2025.07.07.663562v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhj055"},{"key":"2025071203401198000_2025.07.07.663562v1.13","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0460-12.2012"},{"key":"2025071203401198000_2025.07.07.663562v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1625"},{"key":"2025071203401198000_2025.07.07.663562v1.15","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-018-3341-2"},{"key":"2025071203401198000_2025.07.07.663562v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3443"},{"key":"2025071203401198000_2025.07.07.663562v1.17","doi-asserted-by":"crossref","first-page":"e36246","DOI":"10.7554\/eLife.36246","article-title":"Inhibition gates supralinear Ca2+ signaling in Purkinje cell dendrites during practiced movements","volume":"7","year":"2018","journal-title":"Elife"},{"key":"2025071203401198000_2025.07.07.663562v1.18","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4823-05.2006"},{"key":"2025071203401198000_2025.07.07.663562v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00593-7"},{"key":"2025071203401198000_2025.07.07.663562v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80379-7"},{"key":"2025071203401198000_2025.07.07.663562v1.21","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00779.2018"},{"key":"2025071203401198000_2025.07.07.663562v1.22","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1999.00887.x"},{"issue":"7","key":"2025071203401198000_2025.07.07.663562v1.23","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/0028-3908(84)90272-7","article-title":"THIP, a specific and clinically active GABA agonist","volume":"23","year":"1984","journal-title":"Neuropharmacology"},{"key":"2025071203401198000_2025.07.07.663562v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.05.002"},{"key":"2025071203401198000_2025.07.07.663562v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.04.010"},{"key":"2025071203401198000_2025.07.07.663562v1.26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1184334"},{"key":"2025071203401198000_2025.07.07.663562v1.27","doi-asserted-by":"crossref","unstructured":"Lee V , Maguire J . The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits. 2014 Feb 3;8:3.","DOI":"10.3389\/fncir.2014.00003"},{"key":"2025071203401198000_2025.07.07.663562v1.28","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2013.00186"},{"key":"2025071203401198000_2025.07.07.663562v1.29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006298"},{"key":"2025071203401198000_2025.07.07.663562v1.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.22.12905"},{"key":"2025071203401198000_2025.07.07.663562v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00200-9"},{"key":"2025071203401198000_2025.07.07.663562v1.32","doi-asserted-by":"crossref","unstructured":"Mortensen M , Patel B , Smart TG . GABA Potency at GABA(A) Receptors Found in Synaptic and Extrasynaptic Zones. Front Cell Neurosci. 2012 Jan 20;6:1.","DOI":"10.3389\/fncel.2012.00001"},{"key":"2025071203401198000_2025.07.07.663562v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0856-7"},{"key":"2025071203401198000_2025.07.07.663562v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2012.03.020"},{"key":"2025071203401198000_2025.07.07.663562v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/nature10732"},{"key":"2025071203401198000_2025.07.07.663562v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(00)00442-5"},{"key":"2025071203401198000_2025.07.07.663562v1.37","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.12922"},{"key":"2025071203401198000_2025.07.07.663562v1.38","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.036459"},{"key":"2025071203401198000_2025.07.07.663562v1.39","doi-asserted-by":"crossref","unstructured":"Rothman JS , Silver RA . NeuroMatic: An Integrated Open-Source Software Toolkit for Acquisition, Analysis and Simulation of Electrophysiological Data. Front Neuroinform. 2018 Apr 4;12:14.","DOI":"10.3389\/fninf.2018.00014"},{"key":"2025071203401198000_2025.07.07.663562v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108338"},{"key":"2025071203401198000_2025.07.07.663562v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.03.005"},{"key":"2025071203401198000_2025.07.07.663562v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.08.004"},{"key":"2025071203401198000_2025.07.07.663562v1.43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1997.tb01630.x"},{"key":"2025071203401198000_2025.07.07.663562v1.44","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1256-21.2022"},{"issue":"20","key":"2025071203401198000_2025.07.07.663562v1.45","doi-asserted-by":"crossref","first-page":"12617","DOI":"10.3390\/ijms232012617","article-title":"Abnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse","volume":"23","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2025071203401198000_2025.07.07.663562v1.46","doi-asserted-by":"crossref","unstructured":"Zhang K , Yang Z , Gaffield MA , Gross GG , Arnold DB , Christie JM . Molecular layer disinhibition unlocks climbing-fiber-instructed motor learning in the cerebellum. bioRxiv [Preprint]. 2023 Aug 4:2023.08.04.552059.","DOI":"10.1101\/2023.08.04.552059"},{"key":"2025071203401198000_2025.07.07.663562v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2009.08.010"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.07.663562","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:00:31Z","timestamp":1782277231000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.07.07.663562"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,10]]},"references-count":47,"URL":"https:\/\/doi.org\/10.1101\/2025.07.07.663562","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41598-025-31919-w","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,7,10]]},"subtype":"preprint"}}