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

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.

Lack of anticipatory behavior in Gpr88 knockout mice showed by automatized home cage phenotyping

“…This is consistent with the prominent expression of GPR88 in both striatum and cortex . This conclusion also fully accords our recent discovery of specific GPR88 expression in layer 4 of the somatosensory cortex, paralleling delayed sensory processing in Gpr88 −/− mice, as well as our recent fMRI data from Gpr88 −/− mice indicating disrupted functional connectivity predominantly at the level motor and sensory cortices, as well as the striatum in live mutant mice . In further support of our interpretation, the ventral striatum was shown activated in response to ingestive behavior, and dopamine levels in lateral hypothalamic area and the nucleus accumbens are associated with anticipatory and consummatory phases of feeding .…”

Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

“…11,12 GPR88 has also been found in other regions of the brain, including the cerebral cortex, amygdala, and hypothalamus. 13–17 In the striatum, GPR88 is expressed at postsynaptic sites in medium spiny neurons (MSNs) of both direct and indirect pathways. 15 A number of studies using GPR88 knockout (KO) mice have suggested that genetic ablation of GPR88 induces a state of hypersensitivity to the dopamine system, and the receptor is implicated in disease states such as schizophrenia and anxiety.…”

Neuron-specific cilia loss alters locomotor responses to amphetamine

“…Notably, cilia in midbrain dopaminergic and NAc GABAergic neurons express different complements of neuromodulatory receptors. For example, both MCHR1 and GPR88 are enriched in cilia in NAc, but are not detected in cilia on midbrain dopaminergic neurons [16,17,25] The results show that cilia ablation on either GAD2-GABAergic or dopaminergic neurons attenuates the locomotor stimulant effect of acute amphetamine. In contrast, cilia ablation on GAD2-GABAergic neurons enhances sensitization of the locomotor stimulant effect of repeated amphetamine, whereas ablation on dopaminergic neurons has no effect.…”

“…Across organ systems, cilia play a variety of signaling roles, largely related to sensing extracellular cues. Consistent with these roles, neuronal cilia express a variety of G protein-coupled receptors (GPCRs), several of which are rarely expressed outside of cilia [16][17][18]. Importantly, several of these GPCRs modulate behaviors related to drugs of abuse.…”

“…Importantly, several of these GPCRs modulate behaviors related to drugs of abuse. For example, the receptor for melanin-concentrating hormone (MCHR1) modulates responses to psychostimulants, and the orphan GPCR, GPR88, modulates alcohol intake [16,[19][20][21][22]. To date, however, the role or necessity of neuronal cilia in responses to drugs of abuse is essentially unknown.…”