Developmental and adult expression patterns of the G‐protein‐coupled receptor GPR88 in the rat: Establishment of a dual nuclear–cytoplasmic localization

Abstract

GPR88 is a neuronal cerebral orphan G-protein-coupled receptor (GPCR) that has been linked to various psychiatric disorders. However, no extensive description of its localization has been provided so far. Here, we investigate the spatiotemporal expression of the GPR88 in prenatal and postnatal rat tissues by using in situ hybridization and immunohistochemistry. GPR88 protein was initially detected at embryonic day 16 (E16) in the striatal primordium. From E16-E20 to adulthood, the highest expression levels of both protein and mRNA were observed in striatum, olfactory tubercle, nucleus accumbens, amygdala, and neocortex, whereas in spinal cord, pons, and medulla GPR88 expression remains discrete. We observed an intracellular redistribution of GPR88 during cortical lamination. In the cortical plate of the developing cortex, GPR88 presents a classical GPCR plasma membrane/cytoplasmic localization that shifts, on the day of birth, to nuclei of neurons progressively settling in layers V to II. This intranuclear localization remains throughout adulthood and was also detected in monkey and human cortex as well as in the amygdala and hypothalamus of rats. Apart from the central nervous system, GPR88 was transiently expressed at high levels in peripheral tissues, including adrenal cortex (E16-E21) and cochlear ganglia (E19-P3), and also at moderate levels in retina (E18-E19) and spleen (E21-P7). The description of the GPR88 anatomical expression pattern may provide precious functional insights into this novel receptor. Furthermore, the GRP88 nuclear localization suggests nonclassical GPCR modes of action of the protein that could be relevant for cortical development and psychiatric disorders. J. Comp. Neurol. 524:2776-2802, 2016. © 2016 Wiley Periodicals, Inc.

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

“…Reward anticipation neural networks involve both the striatum and cortical regions including visual association cortex and the somatosensory cortex and the fact that Gpr88 −/− mice did not anticipate the water access suggests a possible alteration of this neural network. 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 .…”

“…This is consistent with the prominent expression of GPR88 in both striatum and cortex. 22,38 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, 39 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. 40 In further support of our interpretation, the ventral striatum was shown activated in response to ingestive behavior, 41,42 and dopamine levels in lateral hypothalamic area and the nucleus accumbens are associated with anticipatory and consummatory phases of feeding.…”

Remodeling of Sensorimotor Brain Connectivity in Gpr88-Deficient Mice

“…S1a). We observed the receptor expressed in the layers 4 and 5 of the somatosensory cortex (SS), caudate-putamen (CP), amygdala, nucleus accumbens (ACB), and olfactory tubercle (OT) in support of several previously reported literatures (Becker et al, 2008;Ghate et al, 2007;Massart et al, 2016;Mizushima et al, 2000;Van Waes et al, 2011).…”

“…GPR88 is a striatal-enriched G protein-coupled receptor, expressed in rodents, monkeys, and humans during development and in adulthood (Massart et al, 2016). In humans, the Gpr88 gene was associated with bipolar disorders and schizophrenia (Del Zompo et al, 2014), and the potential of GPR88 as a target to treat psychiatric disorders has attracted increasing interest.…”

Expression map of 78 brain-expressed mouse orphan GPCRs provides a translational resource for neuropsychiatric research

“…Notable is the case of GPR88 , whose striatal-enriched distribution described a decade ago 18–21 attracted attention in both academia and industry. The Gpr88 gene deletion in mice revealed multiple roles in behaviors related to striatal 22–26 and sensory cortical 22,27,28 functions with potential implications for both neurological and psychiatric disorders.…”