GPR88 in A_2A receptor‐expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating

Abstract

The orphan receptor, GPR88, is emerging as a key player in the pathophysiology of several neuropsychiatric diseases, including psychotic disorders. Knockout (KO) mice lacking GPR88 throughout the brain exhibit many abnormalities relevant to schizophrenia including locomotor hyperactivity, behavioral hypersensitivity to dopaminergic psychostimulants and deficient sensorimotor gating. Here, we used conditional knockout (cKO) mice lacking GPR88 selectively in striatal medium spiny neurons expressing A2Areceptor to determine neuronal circuits underlying these phenotypes. We first studied locomotor responses of A2AR-Gpr88 KO mice and their control littermates to psychotomimetic, amphetamine, and to selective D1 and D2 receptor agonists, SKF-81297 and quinpirole, respectively. To assess sensorimotor gating performance, mice were submitted to acoustic and visual prepulse inhibition (PPI) paradigms. Total knockout GPR88 mice were also studied for comparison. Like total GPR88 KO mice, A2AR-Gpr88 KO mice displayed a heighted sensitivity to locomotor stimulant effects of amphetamine and SKF-81297. They also exhibited enhanced locomotor activity to quinpirole, which tended to suppress locomotion in control mice. By contrast, they had normal acoustic and visual PPI, unlike total GPR88 KO mice that show impairments across different sensory modalities. Finally, none of the genetic manipulations altered central auditory temporal processing assessed by gap-PPI. Together these findings support the role of GPR88 in the pathophysiology of schizophrenia and show that GPR88 in A2Areceptor expressing neurons modulates psychomotor behavior but not sensorimotor gating.

GPR88 in D1R-Type and D2R-Type Medium Spiny Neurons Differentially Regulates Affective and Motor Behavior

“…Accordingly, CMV- Gpr88 mice have been shown to have altered transcriptional profiles in these structures where both GPR88 and D1R are expressed (Meirsman et al, 2016b). Most importantly, recent studies using CMV- Gpr88 mice have shown impaired multisensory processing (Ehrlich et al, 2018) and sensorimotor gating (Meirsman et al, 2017) that, coupled with altered sensorimotor and cortico-striatal functional connectivity (Arefin et al, 2017), suggest a role of this receptor in the integration and processing of sensory information. Interestingly, it has also been suggested that modifications of the striato-cortical circuitry may underlie the hyperactivity observed in CMV -Gpr88 mice (Arefin et al, 2017).…”

“…Despite the established overall function of striatal GPR88 in brain functions and deficits (in humans and mice), no study to date has directly compared the specific role of GPR88 in D1R-and D2R-MSNs. A conditional KO mouse line for GPR88 in D2R-MSNs was developed in a previous study, using a A 2A R-Cre driver line (A 2A R -Gpr88 mice), and mutant mice showed hyperactive behavior, decreased anxiety-like behaviors and increased locomotor response to dopaminergic agonists (Meirsman et al, 2016a, 2017). In this study, we have generated conditional Gpr88 KO for D1R-MSNs (D1R- Gpr88 mice), and compared behavioral responses of D1R- Gpr88 with those of A 2A R -Gpr88 mice and total KO (CMV- Gpr88 ) mice.…”

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

“…Previous behavioral studies of Gpr88 -/- mice have highlighted deficits mainly related to striatal function, and deficits in sensorimotor gating (Logue et al 2009; Meirsman et al 2017), however responses of these mice to sensory stimuli have not been examined otherwise. We therefore designed a test battery to challenge the integration of olfactory, somatosensory and visual sensory responses, all related to the remarkable receptor expression pattern in the cortex (Figure 8A).…”

Orphan G Protein Coupled Receptors in Affective Disorders

“…Altogether, these findings suggest that GPR88 levels are finely regulated by sophisticated mechanisms that depend on the brain area and most likely involve a variety of signaling cascades. Considering the physiological relevance of GPR88, several lines of GPR88 KO mice were created to assess the gene function globally or in specific neuronal populations [ 88 , 89 , 90 , 202 ]. GPR88 has been shown to be densely expressed in the CeA, a brain region that controls emotional processing.…”