Decoding transcriptomic signatures of Cysteine String Protein alpha-mediated synapse maintenance

Abstract

AbstractSynapse maintenance is essential for generating functional circuitry and decrement in this process is a hallmark of neurodegenerative disease. While we are beginning to understand the basis of synapse formation, much less is known about synapse maintenancein vivo. Cysteine string protein α (CSPα), encoded by theDnajc5gene, is a synaptic vesicle chaperone that is necessary for synapse maintenance and linked to neurodegeneration. To investigate the transcriptional changes associated with synapse maintenance, we performed single nucleus transcriptomics on the cortex of young CSPα knockout (KO) mice and littermate controls. Through differential expression and gene ontology analysis, we observed that both neurons and glial cells exhibit unique signatures in CSPα KO brain. Significantly all neurons in CSPα KO brains show strong signatures of repression in synaptic pathways, while upregulating autophagy related genes. Through visualization of synapses and autophagosomes by electron microscopy, we confirmed these alterations especially in inhibitory synapses. By imputing cell-cell interactions, we found that neuron-glia interactions were specifically increased in CSPα KO mice. This was mediated by synaptogenic adhesion molecules, including the classical Neurexin1-Neuroligin 1 pair, suggesting that communication of glial cells with neurons is strengthened in CSPα KO mice in an attempt to achieve synapse maintenance. Together, this study reveals unique cellular and molecular transcriptional changes in CSPα KO cortex and provides new insights into synapse maintenance and neurodegeneration.Significance statementSynapse maintenance is important for maintaining neuronal circuitry throughout life. However, little is known about molecules that affect synapse maintenancein vivo. CSPα, encoded by theDnajc5gene, is a synaptic vesicle chaperone that is linked to synapse maintenance and neurodegeneration. Here, we show by performing single nucleus transcriptomics of CSPα KO cortex that synapse instability is related to repression in synaptic pathways and elevation of autophagy in neurons. However, we find a heterogeneity of glial responses. Additionally, interactions between neurons and glia are increased in CSPα KO, mediated by synaptogenic adhesion molecules. This study provides a novel perspective on into synapse maintenance and reveals unique cellular and molecular transcriptional changes in CSPα KO brains.