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Astrocytes contribute to olanzapine-mediated reversal of Kleefstra Syndrome-associated neurodevelopmental regression

Karlijn Vermeulen-Kalk,¹ Shan Wang,² Joost Kummeling,¹ Britt Mossink,¹ Kim N. Wijnant,¹ Carlos O. González Jiménez,¹ Zoe J. Frazier,³ Brian J. Rozumny,⁴ Anne O'Donnell-Luria,⁵ Ellen Hanson,⁴ Monica Frega,¹ Katrin Linda,¹ Moritz Negwer,¹ Bas Lendemeijer,⁶ Astrid Oudakker,¹ Monica Pop-Purceleanu,⁷ Joost G.E. Janzing,⁷ Linde van Dongen,⁸ Femke M.S. de Vrij,⁷ Steven A. Kushner,⁶ Ilse van der Werf,² Chantal Schoenmaker,¹ Wouter Oomens,⁸ Siddharth Srivastava,³ Jos I.M. Egger,⁸ Hans van Bokhoven,¹ Dirk Schubert,² Nael Nadif Kasri,¹ and Tjitske Kleefstra¹

Published June 30, 2026 - More info

Kleefstra syndrome (KLEFS1) results from EHMT1 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 fifty-four individuals with KLEFS1. Among sixteen individuals treated with olanzapine, ten exhibited a beneficial response based upon improvement of their adaptive functioning, and four 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 EHMT1^+/– neuronal networks co-cultured with EHMT1^+/– astrocytes, a dysfunction reversible by olanzapine. Mechanistically, EHMT1^+/– 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 S100B in EHMT1^+/– 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.

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