Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination

doi:10.1073/pnas.0703357104

Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination

*Department of Rehabilitation Science, School of Public Health and Health Professions, University at Buffalo, the State University of New York, Buffalo, NY 14214-3079;
^†Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6074; and
^‡The Porter Neuroscience Center, National Institutes of Health, Bethesda, MD 20892-3701

Edited by Michael V. L. Bennett, Albert Einstein College of Medicine, Bronx, NY, and approved June 2, 2007 (received for review April 25, 2007)

Abstract

During late embryonic and early postnatal life, neuromuscular junctions undergo synapse elimination that is modulated by patterns of motor neuron activity. Here, we test the hypothesis that reduced spinal neuron gap junctional coupling decreases temporally correlated motor neuron activity that, in turn, modulates neuromuscular synapse elimination, by using mutant mice lacking connexin 40 (Cx40), a developmentally regulated gap junction protein expressed in motor and other spinal neurons. In Cx40^−/− mice, electrical coupling among lumbar motor neurons, measured by whole-cell recordings, was reduced, and single motor unit recordings in awake, behaving neonates showed that temporally correlated motor neuron activity was also reduced. Immunostaining and intracellular recording showed that the neuromuscular synapse elimination was accelerated in muscles from Cx40^−/− mice compared with WT littermates. Our work shows that gap junctional coupling modulates neuronal activity patterns that, in turn, mediate synaptic competition, a process that shapes synaptic circuitry in the developing brain.

Footnotes

^§To whom correspondence should be addressed at:
Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104-6074.
E-mail: rbaliceg{at}mail.med.upenn.edu
Author contributions: K.E.P., M.J.O., and R.J.B.-G. designed research; K.E.P., Q.C., G.Z.M., and R.J.B.-G. performed research; K.E.P., Q.C., G.Z.M., M.J.O., and R.J.B.-G. analyzed data; and K.E.P. and R.J.B.-G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0703357104/DC1.
Abbreviations:

AchRs,

acetylcholine receptors;

aCSF,

artificial cerebrospinal fluid;

Cx,

connexin;

EDL,

extensor digitorum longus;

EMG,

electromyography;

epp,

endplate potential;

P(n),

postnatal day (n).