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MCT8\/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type\u2013specific pathologies underlying AHDS remain insufficiently defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell\u2013cell communication modeling were integrated with LC-MS\/MS-based TH quantification, immunofluorescence, and RNAscope.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell\u2013cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin\u2013neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Our findings provide the first single-cell\u2013level cortical map of AHDS brain pathology, revealing cilia defects, excitation\u2013inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10507256261475205","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T17:01:48Z","timestamp":1785862908000},"page":"1005-1020","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan\u2013Herndon\u2013Dudley Syndrome Mouse Model"],"prefix":"10.1177","volume":"36","author":[{"given":"Anna","family":"Molenaar","sequence":"first","affiliation":[{"name":"Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany."},{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."},{"name":"Division of Neurobiology of Diabetes, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekta","family":"Pathak","sequence":"additional","affiliation":[{"name":"Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany."},{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Bernecker","sequence":"additional","affiliation":[{"name":"Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany."},{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."},{"name":"Division of Neurobiology of Diabetes, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No\u00e9mi","family":"Mallet","sequence":"additional","affiliation":[{"name":"Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany."},{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Gutierrez-Aguilar","sequence":"additional","affiliation":[{"name":"Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany."},{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"Unidad de Investigaci\u00f3n en Obesidad, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City, Mexico."},{"name":"Subdirecci\u00f3n de Investigaci\u00f3n Cl\u00ednica, Direcci\u00f3n de Investigaci\u00f3n, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n (INCMNSZ), Mexico City, Mexico."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Mencias","sequence":"additional","affiliation":[{"name":"Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany."},{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."},{"name":"Division of Neurobiology of Diabetes, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Lutter","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."},{"name":"Computational Discovery Research, Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meri","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."},{"name":"Institute of Experimental Genetics, Helmholtz Munich, Neuherberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gandhari","family":"Maity-Kumar","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"K\u00fchnen","sequence":"additional","affiliation":[{"name":"German Center for Child and Adolescent Health (DZKJ), Berlin, Germany."},{"name":"Department for Pediatric Endocrinology and Diabetology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany."},{"name":"Berlin Institute of Health, Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Obermayer","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health, Berlin, Germany."},{"name":"Core Unit Bioinformatics (CUBI), Berlin Institute of Health\/Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Opitz","sequence":"additional","affiliation":[{"name":"Department for Pediatric Endocrinology and Diabetology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, Berlin, Germany."},{"name":"Berlin Institute of Health, Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo D.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, Germany."},{"name":"Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilian University Munich (LMU), Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja C.","family":"Schriever","sequence":"additional","affiliation":[{"name":"Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany."},{"name":"Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany."},{"name":"German Center for Diabetes Research, Neuherberg, 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