Synaptic Gpr85 Influences Cerebellar-Granule-Cell Electrical Properties and Light-Induced Behavior in Zebrafish.

GPR85/SREB2 is an exceptionally conserved orphan seven-transmembrane receptor with poorly understood biological function. Here, we combine genetic, imaging, transcriptomic, electrophysiological, and behavioral approaches in zebrafish to uncover the properties and roles of Gpr85 across development and adulthood. We show that, as in mammals, gpr85 is expressed in diverse neuronal populations within the central nervous system, retina, and intestine. Using a fluorochrome-tagged Gpr85 construct expressed in native domains, we provide the first in vivo evidence that Gpr85 is enriched at synaptic sites in both the brain and retina. Transcriptomic profiling of cerebellar granule cells (GCs) lacking Gpr85 reveals gene expression changes consistent with increased neuronal activity. Electrophysiological recordings from cerebellar slices confirm that Gpr85-deficient GCs exhibit heightened excitability. Functionally, Gpr85 loss enhances light-triggered motor responses in larval zebrafish. Together, these findings position Gpr85 as a synapse-enriched modulator of neuronal excitability and sensory-driven behavior, offering new insight into its roles.