{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T22:19:30Z","timestamp":1783462770569,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T00:00:00Z","timestamp":1610409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tuberous sclerosis complex (TSC) is a genetic disease affecting the brain. Neurological symptoms like epilepsy and neurodevelopmental issues cause a significant burden on patients. Both neurons and glial cells are affected by TSC mutations. Previous studies have shown changes in the excitation\/inhibition balance (E\/I balance) in TSC. Astrocytes are known to be important for neuronal development, and astrocytic dysfunction can cause changes in the E\/I balance. We hypothesized that astrocytes affect the synaptic balance in TSC. TSC patient-derived stem cells were differentiated into astrocytes, which showed increased proliferation compared to control astrocytes. RNA sequencing revealed changes in gene expression, which were related to epidermal growth factor (EGF) signaling and enriched for genes that coded for secreted or transmembrane proteins. Control neurons were cultured in astrocyte-conditioned medium (ACM) of TSC and control astrocytes. After culture in TSC ACM, neurons showed an altered synaptic balance, with an increase in the percentage of VGAT+ synapses. These findings were confirmed in organoids, presenting a spontaneous 3D organization of neurons and glial cells. To conclude, this study shows that TSC astrocytes are affected and secrete factors that alter the synaptic balance. As an altered E\/I balance may underlie many of the neurological TSC symptoms, astrocytes may provide new therapeutic targets.<\/jats:p>","DOI":"10.3390\/cells10010134","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T14:28:53Z","timestamp":1610461733000},"page":"134","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Neuron\u2013Glia Interactions in Tuberous Sclerosis Complex Affect the Synaptic Balance in 2D and Organoid Cultures"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8090-766X","authenticated-orcid":false,"given":"Stephanie","family":"Dooves","sequence":"first","affiliation":[{"name":"Department of Child &amp; Youth Psychiatry, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9480-7053","authenticated-orcid":false,"given":"Arianne J. H.","family":"van Velthoven","sequence":"additional","affiliation":[{"name":"Department of Child &amp; Youth Psychiatry, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5938-0365","authenticated-orcid":false,"given":"Linda G.","family":"Suciati","sequence":"additional","affiliation":[{"name":"Department of Child &amp; Youth Psychiatry, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivi M.","family":"Heine","sequence":"additional","affiliation":[{"name":"Department of Child &amp; Youth Psychiatry, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Centre for Neurogenomics and Cognitive Research, Department of Complex Trait Genetics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S1474-4422(15)00069-1","article-title":"Neurological and neuropsychiatric aspects of tuberous sclerosis complex","volume":"14","author":"Curatolo","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nrneurol.2016.81","article-title":"The mTOR signalling cascade: Paving new roads to cure neurological disease","volume":"12","author":"Crino","year":"2016","journal-title":"Nat. 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