Integrative cross-species analysis of GABAergic neuron cell types and their functions in Alzheimer’s disease

Abstract

Abstract Understanding the phenotypic and functional diversity of cerebral cortical GABAergic neurons requires a comprehensive analysis of key transcriptional signatures and neuronal subtype identity. However, the diversity and conservation of GABAergic neurons across multiple mammals remain unclear. Here, we collected the single-nucleus RNA sequencing (snRNA-seq) datasets of cerebral cortex from human, macaque, mouse, and pig to identify the conserved neuronal cell types across species. After systematic analysis of the heterogeneity of GABAergic neurons, we defined four major conserved GABAergic neuron subclasses (Inc SST, Inc LAMP5, Inc PVALB, and Inc VIP) across species. We characterized the species-enriched subclasses of GABAergic neurons from four mammals, such as Inc Meis2 in mouse. Then, we depicted the genetic regulatory network (GRNs) of GABAergic neuron subclasses, which showed the conserved and species-specific GRNs for GABAergic neuron cell types. Finally, we investigated the GABAergic neuron subclass-specific expression modules of Alzheimer’s disease (AD)-related genes in GABAergic neuron cell types. Overall, our study reveals the conserved and divergent GABAergic neuron subclasses and GRNs across multiple species and unravels the gene expression modules of AD-risk genes in GABAergic neuron subclasses, facilitating the GABAergic neurons research and clinical treatment.