Genetic evidence that relative synaptic efficacy biases the outcome of synaptic competition

Article metrics

Abstract

Synaptic activity drives synaptic rearrangement in the vertebrate nervous system; indeed, this appears to be a main way in which experience shapes neural connectivity1,2. One rearrangement that occurs in many parts of the nervous system during early postnatal life is a competitive process called ‘synapse elimination’3,4. At the neuromuscular junction, where synapse elimination has been analysed in detail, muscle fibres are initially innervated by multiple axons, then all but one are withdrawn and the ‘winner’ enlarges4,5,6. In support of the idea that synapse elimination is activity dependent, it is slowed or speeded when total neuromuscular activity is decreased or increased, respectively4,7,8,9,10,11,12,13. However, most hypotheses about synaptic rearrangement postulate that change depends less on total activity than on the relative activity of the competitors1,2,3,4,13,14. Intuitively, it seems that the input best able to excite its postsynaptic target would be most likely to win the competition, but some theories and results make other predictions14,15,16,17,18. Here we use a genetic method to selectively inhibit neurotransmission from one of two inputs to a single target cell. We show that more powerful inputs are strongly favoured competitors during synapse elimination.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Activation of gene expression in subsets of motor neurons.
Figure 2: ChAT+ axons are favoured competitors over ChAT- axons at multiply innervated neuromuscular junctions.
Figure 3: ChAT- axons fare worse when pitted against a ChAT+ axon than when pitted against another ChAT- axon.

References

  1. 1

    Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996)

  2. 2

    Sengpiel, F. & Kind, P. C. The role of activity in development of the visual system. Curr. Biol. 12, R818–R826 (2002)

  3. 3

    Lichtman, J. W. & Colman, H. Synapse elimination and indelible memory. Neuron 25, 269–278 (2000)

  4. 4

    Personius, K. E. & Balice-Gordon, R. J. Activity-dependent synaptic plasticity: insights from neuromuscular junctions. Neuroscientist 8, 414–422 (2002)

  5. 5

    Sanes, J. R. & Lichtman, J. W. Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 389–442 (1999)

  6. 6

    Walsh, M. K. & Lichtman, J. W. In vivo time-lapse imaging of synaptic takeover associated with naturally occurring synapse elimination. Neuron 37, 67–73 (2003)

  7. 7

    Benoit, P. & Changeux, J. P. Consequences of tenotomy on the evolution of multiinnervation in developing rat soleus muscle. Brain Res. 99, 354–358 (1975)

  8. 8

    Thompson, W., Kuffler, D. P. & Jansen, J. K. The effect of prolonged, reversible block of nerve impulses on the elimination of polyneuronal innervation of new-born rat skeletal muscle fibers. Neuroscience 4, 271–281 (1979)

  9. 9

    Ding, R., Jansen, J. K., Laing, N. G. & Tonnesen, H. The innervation of skeletal muscles in chickens curarized during early development. J. Neurocytol. 12, 887–919 (1983)

  10. 10

    Thompson, W. Synapse elimination in neonatal rat muscle is sensitive to pattern of muscle use. Nature 302, 614–616 (1983)

  11. 11

    Duxson, M. J. The effect of postsynaptic block on development of the neuromuscular junction in postnatal rats. J. Neurocytol. 11, 395–408 (1982)

  12. 12

    O'Brien, R. A., Ostberg, A. J. & Vrbova, G. Observations on the elimination of polyneuronal innervation in developing mammalian skeletal muscle. J. Physiol. (Lond.) 282, 571–582 (1978)

  13. 13

    Busetto, G., Buffelli, M., Tognana, E., Bellico, F. & Cangiano, A. Hebbian mechanisms revealed by electrical stimulation at developing rat neuromuscular junctions. J. Neurosci. 20, 685–695 (2000)

  14. 14

    Barber, M. J. & Lichtman, J. W. Activity-driven synapse elimination leads paradoxically to domination by inactive neurons. J. Neurosci. 19, 9975–9985 (1999)

  15. 15

    Hata, Y., Tsumoto, T. & Stryker, M. P. Selective pruning of more active afferents when cat visual cortex is pharmacologically inhibited. Neuron 22, 375–381 (1999)

  16. 16

    Costanzo, E. M., Barry, J. A. & Ribchester, R. R. Competition at silent synapses in reinnervated skeletal muscle. Nature Neurosci. 3, 694–700 (2000)

  17. 17

    Ridge, R. M. & Betz, W. J. The effect of selective, chronic stimulation on motor unit size in developing rat muscle. J. Neurosci. 4, 2614–2620 (1984)

  18. 18

    Callaway, E. M., Soha, J. M. & Van Essen, D. C. Competition favouring inactive over active motor neurons during synapse elimination. Nature 328, 422–426 (1987)

  19. 19

    Misgeld, T. et al. Roles of neurotransmitter in synapse formation: development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36, 635–648 (2002)

  20. 20

    Brandon, E. P., Lin, W., D'Amour, K. A., Pizzo, D. P., Dominguez, B., Sugiura, Y., Thode, S., Ko, C. P., Thal, L. J., Gage, F. H. & Lee, K. F. Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. J. Neurosci. 23, 539–549 (2003)

  21. 21

    Metzger, D. & Chambon, P. Site- and time-specific gene targeting in the mouse. Methods 24, 71–80 (2001)

  22. 22

    Guo, C., Yang, W. & Lobe, C. G. A Cre recombinase transgene with mosaic, widespread tamoxifen-inducible action. Genesis 32, 8–18 (2002)

  23. 23

    Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000)

  24. 24

    Lewandoski, M. & Martin, G. R. Cre-mediated chromosome loss in mice. Nature Genet. 17, 223–225 (1997)

  25. 25

    Kasthuri, N. & Lichtman, J. W. The role of neuronal identity in synaptic competition. Nature 424, 426–430 (2003)

  26. 26

    Keller-Peck, C. R., Walsh, M. K., Gan, W. B., Feng, G., Sanes, J. R. & Lichtman, J. W. Asynchronous synapse elimination in neonatal motor units: studies using GFP transgenic mice. Neuron 31, 381–394 (2001)

  27. 27

    Personius, K. E. & Balice-Gordon, R. J. Loss of correlated motor neuron activity during synaptic competition at developing neuromuscular synapses. Neuron 31, 395–408 (2001)

  28. 28

    Buffelli, M., Busetto, G., Cangiano, L. & Cangiano, A. Perinatal switch from synchronous to asynchronous activity of motoneurons: link with synapse elimination. Proc. Natl Acad. Sci. USA 99, 13200–13205 (2002)

  29. 29

    Lakso, M. et al. Targeted oncogene activation by site-specific recombination in transgenic mice. Proc. Natl Acad. Sci. USA 89, 6232–6236 (1992)

  30. 30

    Rodriguez, C. I. et al. High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP. Nature Genet. 25, 139–140 (2000)

Download references

Acknowledgements

We thank T. Misgeld and J. Weiner for comments, and R. Lewis for assistance. This work was supported by grants from the National Institutes of Health to J.R.S. and J.W.L.

Author information

Correspondence to Joshua R. Sanes.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.