Synaptic Targeting of Retrogradely Transported Trophic Factors in Motoneurons: Comparison of Glial Cell Line-Derived Neurotrophic Factor, Brain-Derived Neurotrophic Factor, and Cardiotrophin-1 with Tetanus Toxin

Abstract

Glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and cardiotrophin-1 (CT-1) are the most potent neurotrophic factors for motoneurons, but their fate after retrograde axonal transport is not known. Internalized trophic factors may be degraded, or they may be recycled and transferred to other neurons, similar to the known route of tetanus toxin. We tested whether neonatal rat hypoglossal motoneurons target retrogradely transported trophic factors to synaptic sites on their dendrites within the brainstem and subsequently transfer these trophins across the synaptic cleft to afferent synapses (transsynaptic transcytosis). Motoneurons retrogradely transport from the tongue radiolabeled GDNF, BDNF, and CT-1 as well as tetanus toxin. Quantitative autoradiographic electron microscopy showed that GDNF and BDNF were transported into motoneuron dendrites with labeling densities similar to those of tetanus toxin. Although tetanus toxin accumulated rapidly (within 8 h) at presynaptic sites, GDNF accumulated at synapses more slowly (within 15 h), and CT-1 never associated with synapses. Thus, some retrogradely transported neurotrophic factors are trafficked similarly but not identically to tetanus toxin. Both GDNF and BDNF accumulate at the external (limiting) membrane of multivesicular bodies within proximal dendrites. We conclude that tetanus toxin, GDNF, and BDNF are released from postsynaptic sites and are internalized by afferent presynaptic terminals, thus demonstrating transsynaptic transcytosis. CT-1, however, follows a strict degradation pathway after retrograde transport to the soma. Synaptic and transcytotic trafficking thus are restricted to particular neurotrophic factors such as GDNF and BDNF.

Long-Distance Retrograde Effects of Botulinum Neurotoxin A

“…Retrograde transport and transcytosis have been described previously for tetanus neurotoxin and some trophic factors (von Bartheld, 2004;Deinhardt and Schiavo, 2005;Rind et al, 2005;Deinhardt et al, 2006). For example, rat hypoglossal motoneurons retrogradely transport glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor and subsequently transfer these factors across the synaptic cleft to afferent synapses (Rind et al, 2005).…”

“…For example, rat hypoglossal motoneurons retrogradely transport glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor and subsequently transfer these factors across the synaptic cleft to afferent synapses (Rind et al, 2005). As demonstrated for tetanus neurotoxin, transcytosis may be restricted to specific synaptic inputs.…”

Altered Balance of Glutamatergic/GABAergic Synaptic Input and Associated Changes in Dendrite Morphology after BDNF Expression in BDNF-Deficient Hippocampal Neurons

“…At extrasynaptic sites, it may bind to the low-affinity common neurotrophin receptor (NTR) p75 NTR that, in the presence of sortilin, promotes cell death (Teng and Hempstead, 2004); however, if sorted appropriately (Chen et al, 2005) and concentrated in the vicinity of depolarizing synapses (Hartmann et al, 2001), pro-BDNF is also released in an activity-dependent manner. After cleavage, mature BDNF (14 kDa) binds to presynaptic and postsynaptic tyrosine kinase B (TrkB) receptors to either activate local signaling cascades (Kalb, 2005) or exert transcriptional regulation after being transported to the soma of the presynaptic neuron (Howe and Mobley, 2005;Rind et al, 2005). Both mechanisms could account for modifications of transmitter release from axon terminals.…”

Loss of Leukemia Inhibitory Factor Receptor β or Cardiotrophin-1 Causes Similar Deficits in Preganglionic Sympathetic Neurons and Adrenal Medulla

“…Its deficiency causes increased motoneuron cell loss in spinal cord and brainstem between E13.5 and the first postnatal week, further underscoring the physiological relevance of CT-1 as a trophic factor for embryonic motoneurons. Retrograde axonal transport of CT-1 has been documented (Rind et al, 2005). Whether CT-1 acts on PSNs as a target-derived or local factor remains to be investigated.…”