{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T01:01:07Z","timestamp":1789174867709,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"USPHS","award":["R01 NS38992"],"award-info":[{"award-number":["R01 NS38992"]}]},{"name":"USPHS","award":["T32 HD007032"],"award-info":[{"award-number":["T32 HD007032"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Abnormalities in the mammalian target of the rapamycin (mTOR) pathway have been implicated in numerous developmental brain disorders. While the molecular and histological abnormalities have been described, less is known about alterations in membrane and synaptic excitability with chronic changes in the mTOR pathway. In the present study, we used a conditional mouse model with a deletion of the phosphatase and tensin homologue (Pten-\/-, a negative regulator of mTOR) from cortical pyramidal neurons (CPNs). Whole-cell patch clamp recordings in ex vivo slices examined the intrinsic and synaptic membrane properties of layer II\/III CPNs in normal mice treated with rapamycin for four weeks, and Pten-\/- mice with and without chronic treatment with rapamycin. Compared with control mice, CPNs from Pten-\/- mice demonstrated increased membrane capacitance and time constant in association with increased neuronal somatic size, reduced neuronal firing, and decreased frequency of spontaneous and miniature inhibitory postsynaptic currents, consistent with decreased pre-synaptic GABA release. Rapamycin treatment for four weeks prevented these changes in Pten-\/- mice. CPNs from normal mice chronically treated with rapamycin, compared with CPNs from na\u00efve mice, showed reduced capacitance and time constant, increased input resistance, and changes in inhibitory synaptic inputs, consistent with increased pre-synaptic GABA release. These results support the concept that Pten deletion results in significant changes in inhibitory inputs onto CPNs, and these alterations can be prevented with chronic rapamycin treatment. In addition, normal mice treated with rapamycin also display altered membrane and synaptic properties. These findings have potential implications for the treatment of neurological disorders associated with mTOR pathway dysfunction, such as epilepsy and autism.<\/jats:p>","DOI":"10.3390\/cells14020079","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T07:59:42Z","timestamp":1736409582000},"page":"79","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chronic Rapamycin Prevents Electrophysiological and Morphological Alterations Produced by Conditional Pten Deletion in Mouse Cortex"],"prefix":"10.3390","volume":"14","author":[{"given":"Jason S.","family":"Hauptman","sequence":"first","affiliation":[{"name":"IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Antonios","sequence":"additional","affiliation":[{"name":"IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-7610","authenticated-orcid":false,"given":"Gary W.","family":"Mathern","sequence":"additional","affiliation":[{"name":"IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"},{"name":"Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Levine","sequence":"additional","affiliation":[{"name":"IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cepeda","sequence":"additional","affiliation":[{"name":"IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s00018-009-0163-7","article-title":"Key factors in mTOR regulation","volume":"67","author":"Bai","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.cellsig.2009.01.012","article-title":"Mammalian target of rapamycin complex 1: Signalling inputs, substrates and feedback mechanisms","volume":"21","author":"Dunlop","year":"2009","journal-title":"Cell Signal."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1038\/sj.onc.1207542","article-title":"Target of rapamycin (TOR): An integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression","volume":"23","author":"Fingar","year":"2004","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1158\/0008-5472.CAN-06-4470","article-title":"Nucleophosmin mediates mammalian target of rapamycin-dependent actin cytoskeleton dynamics and proliferation in neurofibromin-deficient astrocytes","volume":"67","author":"Sandsmark","year":"2007","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"409","DOI":"10.2174\/138920310791824093","article-title":"The complexes of mammalian target of rapamycin","volume":"11","author":"Zhou","year":"2010","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3733","DOI":"10.1038\/onc.2010.139","article-title":"Targeting mTOR: Prospects for mTOR complex 2 inhibitors in cancer therapy","volume":"29","author":"Sparks","year":"2010","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Girodengo, M., Ultanir, S.K., and Bateman, J.M. (2022). Mechanistic target of rapamycin signaling in human nervous system development and disease. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.1005631"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/ng.2329","article-title":"De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly","volume":"44","author":"Lee","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.bbapap.2007.08.015","article-title":"Role of mTOR in physiology and pathology of the nervous system","volume":"1784","author":"Swiech","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ma, Q., Chen, G., Li, Y., Guo, Z., and Zhang, X. (2024). The molecular genetics of PI3K\/PTEN\/AKT\/mTOR pathway in the malformations of cortical development. Genes Dis., 11.","DOI":"10.1016\/j.gendis.2023.04.041"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tins.2007.08.006","article-title":"Phosphatase PTEN in neuronal injury and brain disorders","volume":"30","author":"Chang","year":"2007","journal-title":"Trends Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rademacher, S., and Eickholt, B.J. (2019). PTEN in Autism and Neurodevelopmental Disorders. Cold Spring Harb. Perspect. Med., 9.","DOI":"10.1101\/cshperspect.a036780"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Spina Nagy, G., Kawamoto, E.M., and Bridi, J.C. (2021). The role of PTEN signaling in synaptic function: Implications in autism spectrum disorder. Neurosci. Lett., 759.","DOI":"10.1016\/j.neulet.2021.136015"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/ng782","article-title":"Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease","volume":"29","author":"Backman","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/S0959-4388(02)00354-9","article-title":"PTEN function in mammalian cell size regulation","volume":"12","author":"Backman","year":"2002","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1002\/cne.23488","article-title":"PTEN knockdown alters dendritic spine\/protrusion morphology, not density","volume":"522","author":"Haws","year":"2014","journal-title":"J. Comp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.expneurol.2016.02.013","article-title":"Long-term consequences of conditional genetic deletion of PTEN in the sensorimotor cortex of neonatal mice","volume":"279","author":"Gutilla","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.neuron.2012.08.002","article-title":"Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy","volume":"75","author":"Pun","year":"2012","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1111\/j.1528-1167.2011.03280.x","article-title":"Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice","volume":"52","author":"Sunnen","year":"2011","journal-title":"Epilepsia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1242\/dmm.002386","article-title":"Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia","volume":"2","author":"Ljungberg","year":"2009","journal-title":"Dis. Model Mech."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1523\/JNEUROSCI.5685-08.2009","article-title":"Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice","volume":"29","author":"Zhou","year":"2009","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000337229","article-title":"Development and characterization of NEX- Pten, a novel forebrain excitatory neuron-specific knockout mouse","volume":"34","author":"Kazdoba","year":"2012","journal-title":"Dev. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11441","DOI":"10.1523\/JNEUROSCI.1283-12.2012","article-title":"Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission","volume":"32","author":"Weston","year":"2012","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8595","DOI":"10.1523\/JNEUROSCI.0878-17.2017","article-title":"PTEN Loss Increases the Connectivity of Fast Synaptic Motifs and Functional Connectivity in a Developing Hippocampal Network","volume":"37","author":"Barrows","year":"2017","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1523\/JNEUROSCI.3144-14.2015","article-title":"Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive","volume":"35","author":"Williams","year":"2015","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.nbd.2016.09.004","article-title":"Disrupted hippocampal network physiology following PTEN deletion from newborn dentate granule cells","volume":"96","author":"LaSarge","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lasarge, C.L., and Danzer, S.C. (2014). Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front. Mol. Neurosci., 7.","DOI":"10.3389\/fnmol.2014.00018"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/s41380-019-0412-6","article-title":"Pten loss results in inappropriate excitatory connectivity","volume":"24","author":"Skelton","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nguyen, L.H., Xu, Y., Nair, M., and Bordey, A. (2024). The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. eLife, 12.","DOI":"10.7554\/eLife.91010.3"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Weston, M.C., Chen, H., and Swann, J.W. (2014). Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures. Front. Mol. Neurosci., 7.","DOI":"10.3389\/fnmol.2014.00001"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nn.2255","article-title":"Laminar and compartmental regulation of dendritic growth in mature cortex","volume":"12","author":"Chow","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10371","DOI":"10.1523\/JNEUROSCI.1592-09.2009","article-title":"Alterations in cortical excitation and inhibition in genetic mouse models of Huntington\u2019s disease","volume":"29","author":"Cummings","year":"2009","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.neuron.2006.03.023","article-title":"Pten regulates neuronal arborization and social interaction in mice","volume":"50","author":"Kwon","year":"2006","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.brainres.2007.06.074","article-title":"A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice","volume":"1168","author":"Ogawa","year":"2007","journal-title":"Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Rall, W. (1977). Core conductor theory and cable properties of neurons. The Nervous System, Cellular Biology of Neurons, Wiley.","DOI":"10.1002\/cphy.cp010103"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.eplepsyres.2007.09.009","article-title":"Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons","volume":"77","author":"Baybis","year":"2007","journal-title":"Epilepsy Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2170\/jjphysiol.47.11","article-title":"Inwardly rectifying potassium channels: Their molecular heterogeneity and function","volume":"47","author":"Isomoto","year":"1997","journal-title":"Jpn. J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1152\/ajplung.00266.2002","article-title":"Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k","volume":"285","author":"Pesce","year":"2003","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0306-4522(01)00167-1","article-title":"Action potential threshold of hippocampal pyramidal cells in vivo is increased by recent spiking activity","volume":"105","author":"Henze","year":"2001","journal-title":"Neuroscience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8110","DOI":"10.1073\/pnas.130200797","article-title":"Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo","volume":"97","author":"Azouz","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1152\/jn.1984.52.2.244","article-title":"Properties of subthreshold response and action potential recorded in layer V neurons from cat sensorimotor cortex in vitro","volume":"52","author":"Stafstrom","year":"1984","journal-title":"J. Neurophysiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1152\/ajpcell.2000.279.1.C81","article-title":"The effect of rapamycin on single ENaC channel activity and phosphorylation in A6 cells","volume":"279","author":"Yue","year":"2000","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hui, J.B., Silva, J.C.H., Pelaez, M.C., Sevigny, M., Venkatasubramani, J.P., Plumereau, Q., Chahine, M., Proulx, C.D., Sephton, C.F., and Dutchak, P.A. (2022). NPRL2 Inhibition of mTORC1 Controls Sodium Channel Expression and Brain Amino Acid Homeostasis. eNeuro, 9.","DOI":"10.1523\/ENEURO.0317-21.2022"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4345","DOI":"10.1523\/JNEUROSCI.0061-11.2011","article-title":"Pten knockdown in vivo increases excitatory drive onto dentate granule cells","volume":"31","author":"Luikart","year":"2011","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0896-6273(00)80382-7","article-title":"Differences in synaptic GABA(A) receptor number underlie variation in GABA mini amplitude","volume":"19","author":"Nusser","year":"1997","journal-title":"Neuron"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1523\/JNEUROSCI.3625-07.2008","article-title":"Kainate modulates presynaptic GABA release from two vesicle pools","volume":"28","author":"Mathew","year":"2008","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1038\/36103","article-title":"Activity-dependent scaling of quantal amplitude in neocortical neurons","volume":"391","author":"Turrigiano","year":"1998","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1080\/15548627.2019.1637643","article-title":"Autophagy links MTOR and GABA signaling in the brain","volume":"15","author":"Hui","year":"2019","journal-title":"Autophagy"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/epi4.12253","article-title":"Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non-mTOR-mediated etiologies","volume":"3","author":"Cepeda","year":"2018","journal-title":"Epilepsia Open"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1007\/s13311-021-01122-6","article-title":"Precision Therapy for Epilepsy Related to Brain Malformations","volume":"18","author":"Poduri","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1111\/j.1528-1167.2012.03506.x","article-title":"Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target","volume":"53","author":"Galanopoulou","year":"2012","journal-title":"Epilepsia"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.neuropharm.2018.08.002","article-title":"The novel, catalytic mTORC1\/2 inhibitor PQR620 and the PI3K\/mTORC1\/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy","volume":"140","author":"Brandt","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1177\/13623613231154053","article-title":"Distinct patterns of GABAergic interneuron pathology in autism are associated with intellectual impairment and stereotypic behaviors","volume":"27","author":"Dufour","year":"2023","journal-title":"Autism Int. J. Res. Pract."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1016\/j.neubiorev.2012.07.005","article-title":"GABA system dysfunction in autism and related disorders: From synapse to symptoms","volume":"36","author":"Coghlan","year":"2012","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jpsychires.2023.11.014","article-title":"Inhibitory dysfunction and social processing difficulties in autism: A comprehensive narrative review","volume":"169","author":"Parrella","year":"2024","journal-title":"J. Psychiatr. Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Cellot, G., and Cherubini, E. (2014). GABAergic signaling as therapeutic target for autism spectrum disorders. Front. Pediatr., 2.","DOI":"10.3389\/fped.2014.00070"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.neuron.2015.07.033","article-title":"Excitatory\/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders","volume":"87","author":"Nelson","year":"2015","journal-title":"Neuron"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/2\/79\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:25:15Z","timestamp":1759919115000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/2\/79"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,8]]},"references-count":57,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["cells14020079"],"URL":"https:\/\/doi.org\/10.3390\/cells14020079","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,8]]}}}