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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Corpus Striatum / cytology*
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Dendrites / physiology*
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Enzyme Inhibitors / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Green Fluorescent Proteins / metabolism
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In Vitro Techniques
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscarine / pharmacology
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Muscarinic Agonists / pharmacology
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Neurons / cytology
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Neurons / drug effects
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Neurons / radiation effects
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Neurons / ultrastructure*
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Oxidopamine / pharmacology
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Patch-Clamp Techniques / methods
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Potassium Channels, Inwardly Rectifying / physiology*
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Receptor, Muscarinic M1 / deficiency
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Receptor, Muscarinic M1 / physiology*
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Receptors, Dopamine D1 / metabolism
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Receptors, Dopamine D2 / metabolism
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Reserpine / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
Substances
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Enzyme Inhibitors
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Muscarinic Agonists
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Potassium Channels, Inwardly Rectifying
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Receptor, Muscarinic M1
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Green Fluorescent Proteins
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Muscarine
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Reserpine
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Oxidopamine