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

Jun Ding, Jaime N. Guzman, Tatiana Tkatch, Songhai Chen, Joshua A. Goldberg, Philip J. Ebert, Pat Levitt, Charles J. Wilson, Heidi E. Hamm, D. James Surmeier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

200 Scopus citations


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, D 2 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.

Original languageAmerican English
Pages (from-to)832-842
Number of pages11
JournalNature Neuroscience
Issue number6
StatePublished - 16 Jun 2006
Externally publishedYes

Bibliographical note

Funding Information:
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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