Deletion of Glutamate Delta 1 Receptor Leads to Heterogeneous Transcription and Synaptic Gene Alterations Across Brain Regions

Glutamate delta 1 receptor (GluD1) has various functional roles in the brain, such as high-frequency hearing, synapse formation and maintenance, and regulation of cognition disorders and neurodevelopmental disease. However, the underlying molecular mechanism, especially at the genetic level, remains to be elucidated. In this study, we use transcriptomics analysis to define the genetic impact of GluD1 across the brain regions in GluD1 knockout mice. Our results show that GluD1 deletion induced pronounced differences in gene expression both across the four brain regions (cortex, cerebellum, hippocampus, and striatum) and the distinct hippocampal subregions. Despite differences in transcriptional profiles, the differentially expressed genes (DEGs) across all four brain regions show significant enrichment in synaptic signaling pathways, highlighting the critical role of GluD1 in synaptic function. The GluD1 interaction network and its downstream target genes are closely linked to the pathogenesis of intellectual disability (ID) and autism spectrum disorders (ASDs). In conclusion, our work reveals that GluD1 deletion leads to brain-region-specific transcriptional changes and establishes a genetic link between the interaction network with GluD1 and the risk genes for ID and ASD.