The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked human disorder characterized by mutations in the MCT8 gene, critical for thyroid hormone (TH) transport across the blood-brain-barrier (BBB). Such central TH deprivation leads to intellectual disability and movement disorders.To understand disrupted processes and to refine future treatment strategies with TH analogs, we conduced single nucleus RNA sequencing studies in a mouse model engineered to replicate the central TH deficiency of AHDS, featuring a dual deletion of MCT8 and the mouse-specific T4 transporter OATP1C1. Bioinformatical analyses of snRNAseq data from 21-day-old WT and dKO mouse cortices showed an increase in microglia and GABAergic neuronal subtypes, reduced numbers of inhibitory parvalbumin and excitatory Rorb neurons, diminished oligodendrocyte numbers and a clear lineage bifurcation between genotypes. Differential gene expression, cell-cell-communication and gene-set-enrichment analyses further suggested an imbalances in GABAergic versus glutamatergic signaling and compromised primary cilia formation in the dKO cortex.Overall, the molecular signatures and perturbations observed in our murine AHDS model closely align with human AHDS pathologies. The observed imbalances in GABAergic and glutamatergic communication, cilia formation, and specific vulnerabilities in oligodendrocyte lineage dynamics and Rorb neurons may further help us in identifying potential intervention targets for future TH therapeutics that circumvent the TH transporter deficiencies. Last, our data may also guide us in determining the optimal timing for initiating treatment of AHDS patients during critical phases of brain development.