GPR88 in A2A receptor‐expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating

• Published in: The European journal of neuroscience Vol. 46; no. 4; pp. 2026 - 2034
• Main Authors: Meirsman, A. C., Kerchove d'Exaerde, A., Kieffer, B. L., Ouagazzal, A.‐M.
• Format: Journal Article
• Language: English
• Published: Chichester Wiley Subscription Services, Inc 01.08.2017
• Subjects: Amphetamines; Auditory pathways; Channel gating; cross‐modal PPI; D2R‐medium spiny neurons; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; GAP detection; Hyperactivity; Hypersensitivity; Information processing; Life Sciences; Locomotion; Locomotor activity; Mental disorders; Neostriatum; Neurons and Cognition; Psychosis; Quinpirole; Rodents; Schizophrenia; Sensorimotor gating; Spiny neurons; striatum; Visual pathways; D2R-medium spiny neurons; schizophrenia; GAP detection; striatum; cross-modal PPI
• ISSN: 0953-816X; 1460-9568; 1460-9568
• DOI: 10.1111/ejn.13646

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, behavioural hypersensitivity to dopaminergic psychostimulants and deficient sensorimotor gating. Here, we used conditional knockout (cKO) mice lacking GPR88 selectively in striatal medium spiny neurons expressing A2A receptor 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 heightened 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 A2A receptor‐expressing neurons modulates psychomotor behaviour but not sensorimotor gating. The orphan receptor, Gpr88, is selectively and highly expressed in striatal medium spiny neurons (MSNs). Ablation of Gpr88 in the whole brain increases the sensitivity of mice to locomotor stimulant effects of dopamine agonists and impairs acoustic and visual PPI. Ablation of Gpr88 selectively in A2Areceptor‐expressing MSNs produces similar motor phenotypes but had no effect on PPI indicating that the former receptors play prominent role in psychomotor behaviours.