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Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors

Nature Neuroscience volume 15, pages 1547–1555 (2012)Cite this article

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Abstract

The striatum regulates motor control, reward and learning. Abnormal function of striatal GABAergic medium spiny neurons (MSNs) is believed to contribute to the deficits in these processes that are observed in many neuropsychiatric diseases. The orphan G protein–coupled receptor GPR88 is robustly expressed in MSNs and is regulated by neuropharmacological drugs, but its contribution to MSN physiology and behavior is unclear. We found that, in the absence of GPR88, MSNs showed increased glutamatergic excitation and reduced GABAergic inhibition, which promoted enhanced firing rates in vivo, resulting in hyperactivity, poor motor coordination and impaired cue-based learning in mice. Targeted viral expression of GPR88 in MSNs rescued the molecular and electrophysiological properties and normalized behavior, suggesting that aberrant MSN activation in the absence of GPR88 underlies behavioral deficits and its dysfunction may contribute to behaviors observed in neuropsychiatric disease.

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Figure 1: Characterization of Gpr88–Cre-EGFP mice.
Figure 2: Hyperlocomotion and motor deficits in Gpr88Cre/Cre mice.
Figure 3: Impaired cue-based learning by Gpr88Cre/Cre mice.
Figure 4: Increased firing rate in MSNs of freely moving Gpr88Cre/Cre mice.
Figure 5: Reduced GABAergic and enhanced glutamatergic signaling in MSNs of Gpr88Cre/Cre mice.
Figure 6: Alterations in mRNA and intracellular signaling in striatum of Gpr88Cre/Cre mice.
Figure 7: Viral re-expression of GPR88 in striatum restores the molecular properties and behavior.
Figure 8: Intracellular RGS4 activity in MSNs is required for viral-mediated electrophysiological rescue.

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Acknowledgements

The authors thank G. Froelick for assistance with histology, J. Parker for help making the targeting construct, L. Zweifel and M. Carter for helpful discussions, and D. Durnam for editing. This work was supported by grants NS052536, NS060803, HD02274 (N.S.B.), MH086386 (G.S.M. and P.S.A.), DA007278 (G.P.S.) and GM032875 (G.S.M.) from the US National Institutes of Health. A.Q. and E.S. were recipients of Spanish Ministry of Science and Innovation postdoctoral mobility program fellowships.

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Authors and Affiliations

  1. Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA

    Albert Quintana, Ali D Güler, Bryan A Roller & Richard D Palmiter

  2. Department of Pharmacology, University of Washington, Seattle, Washington, USA

    Elisenda Sanz, Matthew J Wanat, Paul S Amieux & G Stanley McKnight

  3. Department of Neurology, University of Washington, Seattle, Washington, USA

    Wengang Wang, Granville P Storey & Nigel S Bamford

  4. Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, Washington, USA

    Matthew J Wanat

  5. Department of Biological Structure, University of Washington, Seattle, Washington, USA

    Anna La Torre

  6. Departments of Pediatrics, Psychology, the Graduate Program in Neurobiology and Behavior, and Center on Human Development and Disability, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA

    Nigel S Bamford

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Contributions

A.Q. and R.D.P. designed the study. R.D.P. generated the Gpr88Cre/Cre mice. A.Q. performed the histological experiments. A.Q. and E.S. performed the RiboTag and biochemical experiments. E.S. performed the microarray experiment and A.Q. analyzed the data. W.W., G.P.S. and M.J.W. performed the in vitro electrophysiological studies and analyzed the data. A.Q. and A.D.G. performed the in vivo electrophysiological experiments and A.D.G. analyzed the data. A.Q. and B.A.R. performed the behavioral experiments and analyzed the data. A.Q. made the viral vectors and performed stereotaxic surgery. A.L.T. performed the neuronal primary culture experiments. P.S.A. and G.S.M. supervised the biochemical experiments. N.S.B. supervised the electrophysiological experiments. R.D.P. supervised the study. A.Q., N.S.B. and R.D.P. wrote the manuscript.

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Correspondence to Richard D Palmiter.

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Quintana, A., Sanz, E., Wang, W. et al. Lack of GPR88 enhances medium spiny neuron activity and alters motor- and cue-dependent behaviors. Nat Neurosci 15, 1547–1555 (2012). https://doi.org/10.1038/nn.3239

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