bioRxiv | 2021
Astrocytic cell adhesion genes linked to schizophrenia promote synaptic programs in neurons
Abstract
Recent genetic discoveries in schizophrenia have highlighted neuronal genes with functions in the synapse. Although emblematic of neurons, the development of synapses and neuronal maturation relies on interactions with glial cells including astrocytes. To study the role of glia-neuron interactions in schizophrenia, we generated RNA sequence data from human pluripotent stem cell (hPSC) derived neurons that were cocultured with glial cells. We found that expression of genes characteristic of astrocytes induced the expression of post-synaptic genetic programs in neurons, consistent with advanced neuronal maturation. We further found that the astrocyte-induced genes in neurons were associated with risk for schizophrenia. To understand how glial cells promoted neuronal maturation, we studied the association of transcript abundances in glial cells to gene expression in neurons. We found that expression of synaptic cell adhesion molecules in glial cells corresponded to induced synaptic transcripts in neurons and were associated with genetic risk for schizophrenia. These included 11 genes in significant GWAS loci and three with direct genetic evidence for the disorder (MAGI2, NRXN1, LRRC4B, and MSI2). Our results suggest that astrocyte-expressed genes with functions in the synapse are associated with schizophrenia and promote synaptic genetic programs in neurons, and further highlight the potential role for astrocyte-neuron interactions in schizophrenia.