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The Journal of Neuroscience, November 25, 2009, 29(47):14942-14955; doi:10.1523/JNEUROSCI.2276-09.2009

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Development/Plasticity/Repair
Distinct Muscarinic Acetylcholine Receptor Subtypes Contribute to Stability and Growth, But Not Compensatory Plasticity, of Neuromuscular Synapses

Megan C. Wright,¹ Srilatha Potluri,¹ Xueyong Wang,² Eva Dentcheva,¹ Dinesh Gautam,³ Alan Tessler,^1,4 Jürgen Wess,³ Mark M. Rich,² and Young-Jin Son¹

¹Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, ²Department of Neuroscience, Cell Biology, and Physiology, Wright State University, Dayton, Ohio 45435, ³Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, and ⁴Department of Neurology, Department of Veterans Affairs Hospital, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Young-Jin Son, Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129. Email: yson{at}drexelmed.edu

Muscarinic acetylcholine receptors (mAChRs) modulate synaptic function, but whether they influence synaptic structure remains unknown. At neuromuscular junctions (NMJs), mAChRs have been implicated in compensatory sprouting of axon terminals in paralyzed or denervated muscles. Here we used pharmacological and genetic inhibition and localization studies of mAChR subtypes at mouse NMJs to demonstrate their roles in synaptic stability and growth but not in compensatory sprouting. M₂ mAChRs were present solely in motor neurons, whereas M₁, M₃, and M₅ mAChRs were associated with Schwann cells and/or muscle fibers. Blockade of all five mAChR subtypes with atropine evoked pronounced effects, including terminal sprouting, terminal withdrawal, and muscle fiber atrophy. In contrast, methoctramine, an M_2/4-preferring antagonist, induced terminal sprouting and terminal withdrawal, but no muscle fiber atrophy. Consistent with this observation, M₂^–/– but no other mAChR mutant mice exhibited spontaneous sprouting accompanied by extensive loss of parental terminal arbors. Terminal sprouting, however, seemed not to be the causative defect because partial loss of terminal branches was common even in the M₂^–/– NMJs without sprouting. Moreover, compensatory sprouting after paralysis or partial denervation was normal in mice deficient in M₂ or other mAChR subtypes. We also found that many NMJs of M₅^–/– mice were exceptionally small and reduced in proportion to the size of parental muscle fibers. These findings show that axon terminals are unstable without M₂ and that muscle fiber growth is defective without M₅. Subtype-specific muscarinic signaling provides a novel means for coordinating activity-dependent development and maintenance of the tripartite synapse.

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Received May 14, 2009; revised Oct. 3, 2009; accepted Oct. 14, 2009.

Correspondence should be addressed to Dr. Young-Jin Son, Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129. Email: yson{at}drexelmed.edu

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