Synapse Specification Goes Retro

Science Signaling  17 Aug 2010:
Vol. 3, Issue 135, pp. ec248
DOI: 10.1126/scisignal.3135ec248

Sharma et al. investigated the role of nerve growth factor (NGF) in the formation of synapses between preganglionic and postganglionic neurons (see also Newbern et al). Immunostaining for synaptophysin (a presynaptic protein) and MAGUK proteins (which are postsynaptic) indicated that the superior cervical ganglia (SCGs) from NGF–/– Bax–/– mice showed fewer presynaptic and postsynaptic specializations than those from Bax–/– mice. In addition, NGF withdrawal from cultures of postganglionic sympathetic neurons resulted in a reduction in the number of MAGUK-positive postsynaptic densities (PSDs), whereas selective application of NGF through a microfluidic system to distal axons, but not to cell bodies and dendrites, increased the number of MAGUK-positive clusters. This effect largely depended on the clustering of preexisting components of PSDs, rather than de novo synthesis of PSD components. To visualize trafficking of NGF with one of its receptors, TrkA, the authors used mice expressing a Flag-tagged form of the NGF receptor TrkA (TrkAFlag). When NGF was selectively applied to the distal axons of sympathetic neurons from these mice, Flag-TrkA–containing endosomes formed and were transported in a retrograde fashion to sites of PSD formation in the cell body. The ability of NGF to induce PSD assembly required the tyrosine kinase activity of TrkA in both the distal axon and the cell body and dendrites, as well as MAPK signaling in the cell body and dendrites and PI3K signaling in the distal axon. Brain-derived neurotrophic factor (BDNF)–p75 signaling can antagonize NGF-TrkA signaling. In contrast to SCGs from NGF–/– Bax–/– mice, those from p75–/– mice had more presynaptic and postsynaptic specializations than those from wild-type mice. After a period of NGF deprivation, treatment with NGF increased PSD assembly when a BDNF-neutralizing antibody was applied to the cell body and dendrites but not the distal axon. Thus, retrograde, long-distance NGF signaling induces postsynaptic assembly in the SCG.

N. Sharma, C. D. Deppmann, A. W. Harrington, C. St. Hillaire, Z.-Y. Chen, F. S. Lee, D. D. Ginty, Long-distance control of synapse assembly by target-derived NGF. Neuron 67, 422–434 (2010). [PubMed]

J. M. Newbern, X. Li, W. D. Snider, Signaling endosomes trigger synapse assembly. Neuron 67, 352–354 (2010). [PubMed]