Nature Neuroscience 9, 832 - 842 (2006)
Published online: 14 May 2006; | doi:10.1038/nn1700
RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletionJun Ding1, Jaime N Guzman1, Tatiana Tkatch1, Songhai Chen2, Joshua A Goldberg3, Philip J Ebert2, Pat Levitt2, 4, Charles J Wilson3, Heidi E Hamm2
& D James Surmeier11
Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA. 2
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA. 3
Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, USA. 4
Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37232, USA.
Correspondence should be addressed to D James Surmeier j-surmeier@northwestern.edu 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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