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RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion

Nature Neuroscience volume 9, pages 832–842 (2006)Cite this article

Abstract

Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D2 dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D2 dopamine receptor modulation of calcium (Ca2+) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M4 muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4—an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.

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Figure 1: Dopamine depletion downregulates the M4 modulation of Ca2+ channels in striatal cholinergic interneurons.
Figure 2: RGS4 mRNAs are upregulated in striatal cholinergic interneurons after dopamine depletion.
Figure 3: Gαo2 mediates the M4 modulation of Ca2+ channels in striatal cholinergic interneurons.
Figure 4: RGS4 protein attenuates M4 receptor modulation of Ca2+ channel currents in striatal cholinergic interneurons.
Figure 5: RGS4 protein shifts the Oxo-M dose response curve.
Figure 6: RGS4 mimics the effect of dopamine depletion.
Figure 7: Cav2.2, SK channel block and muscarinic receptor activation induce similar irregular firing patterns in striatal cholinergic interneurons.
Figure 8: M4 regulation of the spontaneous firing pattern of cholinergic interneurons is attenuated following dopamine depletion.

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Acknowledgements

The authors thank Y. Chen, Q. Ruan, K. Saporito, C. McCoy and S. Ulrich for technical assistance, and C.S. Chan and W. Shen for discussions. Supported by NS 34696 (D.J.S.), the Picower Foundation (D.J.S.), NS 37760 (C.J.W.), F32 NS 050900 (J.A.G.), MH45156 (P.L.), HD15052 (P.L.), the McKnight Foundation (P.L.), National Alliance for Research in Schizophrenia and Depression (P.J.E.) and MH065215 (P.J.E.).

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Authors and Affiliations

  1. Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, 60611, Illinois, USA

    Jun Ding, Jaime N Guzman, Tatiana Tkatch & D James Surmeier

  2. Department of Pharmacology, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Songhai Chen, Philip J Ebert, Pat Levitt & Heidi E Hamm

  3. Department of Biology, University of Texas at San Antonio, San Antonio, 78249, Texas, USA

    Joshua A Goldberg & Charles J Wilson

  4. Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Pat Levitt

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Contributions

J.D. did most of the voltage-clamp and scRT-PCR experiments; he also participated in the writing of the manuscript and in the preparation of the figures. J.N.G. did the slice experiment examining the muscarinic modulation of interneuron spiking. T.T. designed all the primers and did the real-time RT-PCR experiment. J.A.G. and C.J.W. did the slice recording experiments examining the sensitivity of pacemaking to Ca2+ channel and SK channel block. S.C. and H.E.H. provided all the RGS proteins and peptides and did the GTPase activity assay. P.J.E. and P.L. generated the RGS4 OE mice. D.J.S. directed the project, prepared the figures and was responsible for the final manuscript.

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Correspondence to D James Surmeier.

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Supplementary information

Supplementary Fig. 1

RGS4 and 9 are different regulated in mice striatum tissues following domapine depletion by reserpine treatment. (PDF 334 kb)

Supplementary Fig. 2

Two dopamine depletion models produce same effect on M4 modulation of calcium channels. (PDF 1076 kb)

Supplementary Fig. 3 (PDF 5101 kb)

Supplementary Fig. 4 (PDF 656 kb)

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Ding, J., Guzman, J., Tkatch, T. et al. RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion. Nat Neurosci 9, 832–842 (2006). https://doi.org/10.1038/nn1700

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