Editors' ChoiceNeuroscience

Neurons Get the Neuroligin-1 Advantage

Science Signaling  18 Dec 2012:
Vol. 5, Issue 255, pp. ec328
DOI: 10.1126/scisignal.2003886

Neuroligin-1 (NL1) is a transsynaptic cell adhesion molecule present on the postsynaptic side of excitatory synapses. Studies in vitro have indicated that the abundance of NL1 controls the activity of N-methyl-D-aspartate (NMDA)–type glutamate receptors and the number of synapses, with more NL1 promoting both of these events. Although NL1 knockout mice show a similar reduction in NMDA receptor signaling, they do not show alterations in synaptic density or morphology (see Barrow and McAllister). Kwon et al. used in vivo RNA interference strategies to produce mosaic mice with different proportions of neurons lacking NL1, with some mice showing loss of NL1 in most neurons and some showing loss in only a sparse number of neurons. Imaging and electrophysiological analysis of brain slices showed that neurons in which NL1 was knocked down had dendritic spines with altered morphology compared with those of neighboring wild-type neurons and that the frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in the NL1-knockdown neurons. In contrast, spine density and mEPSC frequency were unchanged in total NL1-knockout mice. Electrophysiological analysis after release of caged glutamate at specific sites showed that NL1 deficiency or knockout resulted in reduced NMDA-mediated currents. The success rate of new synapse formation in response to uncaging of glutamate to produce activity-dependent synaptogenesis was reduced in neurons in which NL1 was knocked down compared with that in the neighboring neurons or the neurons of NL1-knockout mice. Thus, sparse, but not global, absence of NL1 increased the threshold for activity-dependent synaptogenesis, suggesting that NL1 may confer a competitive advantage in a mixed population of neurons. Coculture experiments with wild-type and NL1-knockout neurons confirmed this hypothesis: Spine density was lower for the NL1-deficient neurons, but only when these cells were cocultured with wild-type neurons. Experiments with interfering RNAs of differing effectiveness confirmed that spine density and mEPSC frequency depended on the amount of NL1, with more NL1 conferring an advantage.

H.-B. Kwon, Y. Kozorovitskiy, W.-J. Oh, R. T. Peixoto, N. Akhtar, J. L. Saulnier, C. Gu, B. L. Sabatini, Neuroligin-1–dependent competition regulates cortical synaptogenesis and synapse number. Nat. Neurosci. 15, 1667–1674 (2012). [PubMed]

S. L. Barrow, A. K. McAllister, Neuroligins help dendrites keep up with the Joneses. Nat. Neurosci. 15, 1609–1611 (2012). [PubMed]