15Q13.3 MICRODELETION ALTERS THE TRANSCRIPTOME OF DEVELOPING ASTROCYTES

Deletion of the 15q13.3 region is associated with a spectrum of neurodevelopmental disorders (NDDs), including developmental delay, intellectual disability, epilepsy, autism spectrum disorder, and schizophrenia. While deficits in excitatory and inhibitory neuronal populations are well characterized in this microdeletion, the contribution of glial cells remains comparatively understudied. Given that glial dysfunction, including reduction in astrocytes and white matter abnormalities, has been implicated in NDD pathogenesis, we sought to investigate glial involvement in the 15q13.3 microdeletion. We used single-cell sequencing (scRNA-seq) to profile the P2 cortex of the heterozygous 15q13.3 mouse model, and we examined glial protein expression across development. Our scRNA‑seq analysis revealed that 15q13.3 genes are expressed in astrocytes and oligodendrocytes during early postnatal development. Differential gene expression analysis identified astrocytes as the most affected cell type, exhibiting the largest number of transcriptional changes. Downregulated genes in astrocytes were enriched for pathways related to synapse structure, organization, and neural activity, whereas upregulated genes were associated with gliogenesis and cell death. Pseudotime trajectory analysis further demonstrated altered astrocyte maturation in the microdeletion. Consistent with these early transcriptional disruptions, immunohistochemical analysis at P2 showed a significant reduction in glial progenitor populations. Notably, astrocyte and mature oligodendrocyte numbers were comparable to controls in the adult cortex suggesting compensation. Overall, our findings indicate that the 15q13.3 microdeletion affects early glial development, particularly astrocyte maturation, and highlight the need to investigate how early glial perturbations may contribute to long‑term functional and behavioral outcomes.