{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:49:46Z","timestamp":1791946186300,"version":"4.3.4"},"reference-count":68,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":48,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Organization for Health Research and Development ZonMw","award":["91718310,10250022110003"],"award-info":[{"award-number":["91718310,10250022110003"]}]},{"DOI":"10.13039\/100031366","name":"ERA-Net NEURON","doi-asserted-by":"crossref","award":["102 SYNSCHIZ"],"award-info":[{"award-number":["102 SYNSCHIZ"]}],"id":[{"id":"10.13039\/100031366","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"crossref","award":["201806210076"],"award-info":[{"award-number":["201806210076"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100014370","name":"Simons Foundation Autism Research Initiative","doi-asserted-by":"crossref","award":["890042"],"award-info":[{"award-number":["890042"]}],"id":[{"id":"10.13039\/100014370","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NWO","award":["024.003.001"],"award-info":[{"award-number":["024.003.001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,17]]},"abstract":"<jats:p>\n                    Kleefstra syndrome (KLEFS1) results from\n                    <jats:italic>EHMT1<\/jats:italic>\n                    haploinsufficiency and is characterized by variable neurodevelopmental delays and psychopathology. Developmental regression, marked by the sudden loss of previously acquired daily life skills during late puberty or early adulthood, has emerged as a severe complication in individuals with KLEFS1. To investigate the clinical and molecular mechanisms underlying developmental regression and assess the therapeutic potential of olanzapine, we conducted a sequential study in an international cohort of 54 individuals with KLEFS1. Among 16 individuals treated with olanzapine, 10 exhibited a beneficial response based upon improvement of their adaptive functioning, and 4 showed temporary improvement. These clinical findings informed preclinical studies using human induced pluripotent stem cell-derived and ex-vivo cortical slices from a mouse model of KLEFS1. We identified hyperactivity in\n                    <jats:italic>EHMT1<\/jats:italic>\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    neuronal networks cocultured with\n                    <jats:italic>\n                      EHMT1\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    astrocytes, a dysfunction reversible by olanzapine. Mechanistically,\n                    <jats:italic>\n                      EHMT1\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    astrocytes displayed elevated levels of S100B, a neuroinflammatory marker contributing to neuronal network hyperactivity. Notably, olanzapine treatment reduced S100B levels, and pharmacological inhibition or genetic knockdown of\n                    <jats:italic>S100B<\/jats:italic>\n                    in\n                    <jats:italic>EHMT1<\/jats:italic>\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    astrocytes was sufficient to rescue the neuronal hyperactivity phenotype. These findings underscore a critical role for astrocytes in KLEFS1 pathophysiology and identify a potential cellular target for olanzapine in mitigating developmental regression.\n                  <\/jats:p>\n                  <jats:p>Kleefstra syndrome (KLEFS1) involves neurodevelopmental regression. Olanzapine improved symptoms in some patients, potentialy by reducing astrocyte-driven brain hyperactivity linked to elevated S100\u03b2 levels.<\/jats:p>","DOI":"10.1172\/jci195803","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:15:08Z","timestamp":1782843308000},"source":"Crossref","is-referenced-by-count":2,"title":["Astrocytes contribute to olanzapine-mediated reversal of kleefstra syndrome-associated neurodevelopmental regression"],"prefix":"10.1172","volume":"136","author":[{"given":"Karlijn","family":"Vermeulen-Kalk","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Radboud UMC, Nijmegen, Netherlands."},{"name":"Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, Netherlands."},{"name":"Department for Intellectual Disabilities, Karakter Child and Adolescent Psychiatry, Ede, 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