Optic Tectum

Studies using the optic tectum have significantly contributed to our understanding of the many roles of neurotrophins in synaptogenesis76,77. The retinal ganglion cells (RGC) extend a single axon to the optic tectum in lower vertebrates or the lateral geniculate nucleus (LGN) in higher vertebrates. A remarkable early finding was that injection of BDNF into the optic tectum of live Xenopus tadpoles increased the arborization of RGC axon terminals, which express TrkB78. BDNF also regulates RGC dendritic growth, but this regulation is more complex. Target (tectum)-derived BDNF increased dendritic arbor complexity while local (retina)-derived BDNF inhibited dendritic arborization79,80.

However, an enhancement in axon terminal arborization does not necessarily lead to an increase in synapse number. By labeling presynaptic sites with GFP-synaptobrevin and axonal terminals with DsRed, Alsina et al. showed that injection of BDNF enhanced RGC terminal arbor complexity as well as the density of GFP-synaptobrevin identified at presynaptic sites in vivo81. Conversely, inhibition of endogenous tectal BDNF by function-blocking antibodies significantly enhanced GFP-synaptobrevin cluster elimination, and this was in parallel with an increase in branch elimination82.

Neuronal/synaptic activity also regulates axon terminal arborization, as well as synapse number. Global activity such as action potentials may preferentially affect terminal arborization. Time-lapse imaging showed that retinal activity blockade by tetrodotoxin (TTX) led to an increase in both addition and elimination of terminal branches, reducing the stabilization of axon terminals. In contrast, BDNF promoted axonal arborization by increasing branch addition and lengthening, without affecting branch elimination, and this effect is activity independent83. Local, synaptic activity may preferentially affect synapse number. Tectal injection of the NMDA receptor antagonists APV or MK801 reduced synapse number, as reflected by GFP-synaptobrevin cluster, but did not influence axon branch addition or elimination. Co-injection of NMDA receptor antagonists with BDNF prevented synaptic de-stabilization82. Therefore BDNF influences RGC synaptogenesis by not only promoting morphological maturation of RGC axons but also by stabilizing synapses.

Taken together, these studies provide direct correlations between structural changes and synapse formation, both of which are regulated by BDNF. However, it is unclear whether newly formed or stabilized synapses are physiologically active. Moreover, the signaling cascades mediating morphological changes induced by neurotrophins are poorly understood. Recent studies that examine actin cytoskeletal dynamics suggest that F-actin stabilization and/or polymerization may be a candidate since pre- and postsynaptic changes of actin directly influences the stability of developing synapses84,85.

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