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In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+\u2009interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+\u2009interneurons, including an abnormal <jats:italic>NKCC1\/KCC2<\/jats:italic> ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABA<jats:sub>A<\/jats:sub> receptor subunits, <jats:italic>GABRA1<\/jats:italic>, and upregulation of <jats:italic>GABRA2.<\/jats:italic> Further exploration of SST+\u2009interneurons revealed altered localization patterns of SST+\u2009interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+\u2009interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.<\/jats:p>","DOI":"10.1007\/s00401-024-02737-7","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T16:01:47Z","timestamp":1715097707000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex"],"prefix":"10.1007","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0676-4701","authenticated-orcid":false,"given":"Mirte","family":"Scheper","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederik N. 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