Single-nucleus RNA sequencing reveals cell type-specific transcriptome alterations of Down syndrome hippocampus using the Dp16 mouse model

Background Down syndrome (DS), the most frequently occurring human chromosomal disorder, is caused by trisomy 21. The exact molecular effects of trisomy on certain cell populations in the brain remain poorly understood. Objective The purpose of this study was to investigate the effects of trisomy on the transcriptomes of various types of neurons and nonneuronal cells in the hippocampus. Methods A total of 8993 nuclei from the WT and 6445 nuclei from the Dp16 hippocampus were analyzed by single-nucleus RNA sequencing (snRNA-seq). Cell clustering was achieved by the Seurat program. Results Hippocampal cells were grouped into multiple neuronal and nonneuronal populations. Only a limited number of trisomic genes were upregulated (q < 0.001) over 1.25-fold in a specific type of hippocampal cell. Specifically, deregulation of genes associated with synaptic signaling and organization was observed in multiple cell populations, including excitatory neurons, oligodendrocytes, and microglia. This observation suggests the potential importance of synapse deficits in DS. Interestingly, GO annotation of the upregulated genes suggested potential activation of the immune system by hippocampal excitatory neurons. Fewer trisomic genes were altered in nonneuronal cells than in neurons. Notably, microglial transcriptome analysis revealed significantly (q < 0.001) increased expression of C1qb and C1qc , which suggested potential involvement of complement-mediated synapse loss mediated by microglia in DS. Conclusion The trisomy-related hippocampal deficits should be driven by a small amount, not all, of the trisomic genes in a specific type of cell. Our work may help to narrow down both the molecular and cellular targets for future gene therapies in DS.