Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing

Brain Struct Funct. 2018 Apr;223(3):1275-1296. doi: 10.1007/s00429-017-1547-3. Epub 2017 Nov 6.

Abstract

GPR88 is an orphan G-protein coupled receptor originally characterized as a striatal-enriched transcript and is a potential target for neuropsychiatric disorders. At present, gene knockout studies in the mouse have essentially focused on striatal-related functions and a comprehensive knowledge of GPR88 protein distribution and function in the brain is still lacking. Here, we first created Gpr88-Venus knock-in mice expressing a functional fluorescent receptor to fine-map GPR88 localization in the brain. The receptor protein was detected in neuronal soma, fibers and primary cilia depending on the brain region, and remarkably, whole-brain mapping revealed a yet unreported layer-4 cortical lamination pattern specifically in sensory processing areas. The unique GPR88 barrel pattern in L4 of the somatosensory cortex appeared 3 days after birth and persisted into adulthood, suggesting a potential function for GPR88 in sensory integration. We next examined Gpr88 knockout mice for cortical structure and behavioral responses in sensory tasks. Magnetic resonance imaging of live mice revealed abnormally high fractional anisotropy, predominant in somatosensory cortex and caudate putamen, indicating significant microstructural alterations in these GPR88-enriched areas. Further, behavioral analysis showed delayed responses in somatosensory-, visual- and olfactory-dependent tasks, demonstrating a role for GPR88 in the integration rather than perception of sensory stimuli. In conclusion, our data show for the first time a prominent role for GPR88 in multisensory processing. Because sensory integration is disrupted in many psychiatric diseases, our study definitely positions GPR88 as a target to treat mental disorders perhaps via activity on cortical sensory networks.

Keywords: Gpr88; Gpr88-Venus fluorescent protein; Knock-in and knockout mice; Layer 4 cortex; Orphan G protein-coupled receptor; Primary cilia.

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Brain / cytology
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Brain Mapping*
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Discrimination, Psychological / physiology
  • Endodeoxyribonucleases
  • Female
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
  • HEK293 Cells
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism*
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / metabolism
  • Odorants
  • Phosphopyruvate Hydratase / metabolism
  • Psychomotor Performance / physiology
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Recognition, Psychology / physiology
  • Transfection

Substances

  • Bacterial Proteins
  • Carrier Proteins
  • Gpr88 protein, mouse
  • Luminescent Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • yellow fluorescent protein, Bacteria
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • GRK2 protein, human
  • G-Protein-Coupled Receptor Kinase 2
  • Endodeoxyribonucleases
  • RBBP8 protein, human
  • ADP-Ribosylation Factors
  • Arl13b protein, human
  • Phosphopyruvate Hydratase