Neurotrophins modulate neuron-glia interactions at a vertebrate synapse.
Neurotrophins are important modulators of synaptic function at both developing and mature synapses in the CNS and PNS. At the neuromuscular junction (NMJ), neurotrophins, as well as perisynaptic Schwann cells (PSCs) are critical for the long-term maintenance and stability of the synapse. Considering this correlation and the acute interactions that occur at the synapse between PSCs and the nerve terminal, we wondered if neurotrophins could also be involved in neuron-glia signalling. To test if neurotrophins were able to signal to PSCs we used brief applications of neurotrophin-3 (NT-3), brain-derived neurotophic factor (BDNF) or nerve growth factor (NGF; 100 ng/mL). Soleus muscles of mice were incubated with the Ca(2+) indicator Fluo-4AM and Ca(2+) responses in PSCs were elicited through nerve stimulation (50 Hz, 30 s). Our results indicate that acute application of both NT-3 and BDNF, but not NGF, increased PSC Ca(2+) responses. Investigation of the mechanisms involved in these increases revealed distinct pathways for BDNF and NT-3. BDNF increased PSC responsiveness through potentiation of ATP responses while NT-3 modulated muscarinic acetylcholine receptor signalling. Using local applications of the neurotrophins, we found that both neurotrophins were able to elicit Ca(2+) responses in PSCs where BDNF used a phospholipase C-inositol 1,4,5-triphosphate (PLC-IP(3)) mechanism, while NT-3 required extracellular Ca(2+). Our results demonstrate a neurotrophin-dependent modulation of neuron-glia signalling through differential mechanisms employed by NT-3 and BDNF. Hence, neurotrophins precisely and differentially regulate PSC functions through modulation of either purinergic or cholinergic signalling pathways.
Todd
Keith J
KJ
Département de physiologie and Centre de Recherche en Sciences Neurologiques, Faculté de médecine, Université de Montréal, C.P. 6128 Succ. Centre-ville, Montréal, Québec, Canada, H3C 3J7.
Auld
Daniel S
DS
Robitaille
Richard
R
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology; D009414:Nerve Growth Factors / Q000145:classification / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects*; D014966:Xanthenes / Q000378:metabolism
D000814:Aniline Compounds; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; C409648:Fluo 4; D018727:Muscarinic Antagonists; D009414:Nerve Growth Factors; D014966:Xanthenes; D001285:Atropine; D000255:Adenosine Triphosphate; D002118:Calcium