Abstract
Dopamine-depleting lesions of the striatum that mimic Parkinson's disease induce a profound pruning of spines and glutamatergic synapses in striatopallidal medium spiny neurons, leaving striatonigral medium spiny neurons intact. The mechanisms that underlie this cell type–specific loss of connectivity are poorly understood. The Kir2 K+ channel is an important determinant of dendritic excitability in these cells. Here we show that opening of these channels is potently reduced by signaling through M1 muscarinic receptors in striatopallidal neurons, but not in striatonigral neurons. This asymmetry could be attributed to differences in the subunit composition of Kir2 channels. Dopamine depletion alters the subunit composition further, rendering Kir2 channels in striatopallidal neurons even more susceptible to modulation. Reduced opening of Kir2 channels enhances dendritic excitability and synaptic integration. This cell type–specific enhancement of dendritic excitability is an essential trigger for synaptic pruning after dopamine depletion, as pruning was prevented by genetic deletion of M1 muscarinic receptors.
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Acknowledgements
We thank Q. Ruan, K. Saporito and C. McCoy for technical assistance, and N. Heintz and P. Greengard of Rockefeller University for supplying BAC transgenic mice. This work was supported by NIH grant NS 34696 and a grant from the Picower Foundation.
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W.S. designed and performed all electrophysiological experiments, analyzed the data, prepared the figures, and wrote the manuscript with D.J.S. X.T. did the immunocytochemical experiment examining the dendritic expression of Kir2.1 and 2.3 subunits. M.D. performed two-photon laser scanning microcopy to examine dendritic spine morphology after DA depletion. S.U. designed Kir2 primers and did the scRT-PCR experiment. T.T. performed the real-time RT-PCR experiment. N.M.N. generated the M1 muscarinic receptor knockout mice. D.J.S. directed the project, prepared the figures and was responsible for the final manuscript.
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Shen, W., Tian, X., Day, M. et al. Cholinergic modulation of Kir2 channels selectively elevates dendritic excitability in striatopallidal neurons. Nat Neurosci 10, 1458–1466 (2007). https://doi.org/10.1038/nn1972
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DOI: https://doi.org/10.1038/nn1972
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