Neurotransmission selectively regulates synapse formation in parallel circuits in vivo

Nature. 2009 Aug 20;460(7258):1016-20. doi: 10.1038/nature08236.


Activity is thought to guide the patterning of synaptic connections in the developing nervous system. Specifically, differences in the activity of converging inputs are thought to cause the elimination of synapses from less active inputs and increase connectivity with more active inputs. Here we present findings that challenge the generality of this notion and offer a new view of the role of activity in synapse development. To imbalance neurotransmission from different sets of inputs in vivo, we generated transgenic mice in which ON but not OFF types of bipolar cells in the retina express tetanus toxin (TeNT). During development, retinal ganglion cells (RGCs) select between ON and OFF bipolar cell inputs (ON or OFF RGCs) or establish a similar number of synapses with both on separate dendritic arborizations (ON-OFF RGCs). In TeNT retinas, ON RGCs correctly selected the silenced ON bipolar cell inputs over the transmitting OFF bipolar cells, but were connected with them through fewer synapses at maturity. Time-lapse imaging revealed that this was caused by a reduced rate of synapse formation rather than an increase in synapse elimination. Similarly, TeNT-expressing ON bipolar cell axons generated fewer presynaptic active zones. The remaining active zones often recruited multiple, instead of single, synaptic ribbons. ON-OFF RGCs in TeNT mice maintained convergence of ON and OFF bipolar cells inputs and had fewer synapses on their ON arbor without changes to OFF arbor synapses. Our results reveal an unexpected and remarkably selective role for activity in circuit development in vivo, regulating synapse formation but not elimination, affecting synapse number but not dendritic or axonal patterning, and mediating independently the refinement of connections from parallel (ON and OFF) processing streams even where they converge onto the same postsynaptic cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Dendrites / metabolism
  • Female
  • GluK2 Kainate Receptor
  • Glutamic Acid / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / metabolism
  • Retinal Bipolar Cells / cytology
  • Retinal Bipolar Cells / metabolism
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism
  • Synapses / metabolism*
  • Synaptic Transmission / physiology*
  • Tetanus Toxin / genetics
  • Tetanus Toxin / metabolism


  • Receptors, Kainic Acid
  • Tetanus Toxin
  • Glutamic Acid