Gene Expression at the Tripartite Synapse: Bridging the Gap Between Neurons and Astrocytes

Abstract

Astrocytes, a major class of glial cells, are an important element at the synapse where they engage in bidirectional crosstalk with neurons to regulate numerous aspects of neurotransmission, circuit function, and behavior. Mutations in synapse-related genes expressed in both neurons and astrocytes are central factors in a vast number of neurological disorders, making the proteins that they encode prominent targets for therapeutic intervention. Yet, while the roles of many of these synaptic proteins in neurons are well established, the functions of the same proteins in astrocytes are largely unknown. This gap in knowledge must be addressed to refine therapeutic approaches. In this chapter, we integrate multiomic meta-analysis and a comprehensive overview of current literature to show that astrocytes express an astounding number of genes that overlap with the neuronal and synaptic transcriptomes. Further, we highlight recent reports that characterize the expression patterns and potential novel roles of these genes in astrocytes in both physiological and pathological conditions, underscoring the importance of considering both cell types when investigating the function and regulation of synaptic proteins.

Keywords: Astrocyte; Neuron; Synaptic gene expression; Synaptic proteome; Tripartite synapse.

Fig. 1. Astrocytes express many of the same synaptic genes as neurons.

(a) Diagram of process by which synaptic genes commonly expressed by neurons and astrocytes were determined. Gene lists (FPKM ≥1) were obtained from publicly available datasets and processed to obtain unified gene names and IDs. (b) Venn diagram showing the overlap between synaptic proteome, total number of genes expressed by neurons, and astrocytes. (c) Same as B but using the top 500 highest expressing genes in each cell type. (d) Heatmaps of the top 25 highest expressing genes shown as Log2 FPKM enriched in neurons, astrocytes, or common to both cell types. (e) Heatmaps of genes expressed in both neurons and astrocytes, known to play important roles at the synapse that have been predominantly studied in neurons

Fig. 2. Astrocytic and neuronal gene enrichment for cell type-specific and common GO biological processes.

Gene Ontology (GO) terms analysis of the top 500 most highly expressing synaptic genes in each cell type using String database for biological process (BP) in (a) neuron-enriched synaptic genes, (b) astrocyte-enriched synaptic genes, and (c) common synaptic genes to both cell types. GO terms are plotted by gene ratio value and color-coded by −log10 false discovery rate (FDR). Example GO terms are highlighted in bold