RESEARCH HIGHLIGHTS Nature Reviews Neuroscience | AOP, published online 13 August 2014; doi:10.1038/nrn3808
SYNAPTIC PLASTICITY
A homeostatic messenger mutant flies lacking the endostatin domain showed no defects in baseline synaptic transmission but impaired presynaptic homeostasis
At the fly neuromuscular junction (NMJ), inhibition of postsynaptic glutamate receptors leads to a homeo static rise in presynaptic glutamate release to maintain baseline levels of muscle excitation; however, the identity of the retrograde signal that mediates this effect has been unclear. Now, Davis and colleagues show that a cleavage product of Multiplexin — the fly homologue of mammalian collagen XV and XVIII — can act as a transsynaptic messenger that promotes such homeostatic plasticity. To identify potential media tors of homeostatic plasticity, the authors screened mutated flies for impaired homeostatic presynaptic glutamate release at the NMJ fol lowing philanthotoxin-mediated inhibition of postsynaptic glutamate receptors. They identified two trans poson insertions in Multiplexin that inhibited such release. One of these mutations — dmpf 07253 — was also associated with lower NMJ baseline neurotransmission, suggesting that Multiplexin has at least two separate presynaptic functions. Multiplexin, like its collagen homologues, is composed of mul tiple protein domains, including an amino-terminal thrombospondinlike domain and a carboxyterminal endostatin domain, which is released following proteolytic cleavage. Mutant flies lacking the
thrombospondin-like domain had a decrease in baseline neurotransmis sion at the NMJ but near normal presynaptic homeostasis, whereas mutant flies lacking the endostatin domain showed no defects in baseline synaptic transmission but impaired presynaptic homeostasis. This indicates that the two domains each convey one of the two presynaptic functions of Multiplexin. Collagen XV and XVIII can be found in the extracellular matrix, and the authors found that green fluorescent protein-tagged endostatin could also be found on the surface of neurons and muscles when over expressed in these cells. Moreover, overexpression of endostatin in either the presynaptic neuron or postsyn aptic muscle at the NMJ rescued the homeostatic deficit in dmpf 07253 flies, suggesting that fly endostatin may act as a retrograde signalling molecule. To examine the mechanistic effects of endostatin, the authors used flies that exhibit a persistent homeostatic increase in presynaptic glutamate release owing to deletion of the ionotropic glutamate recep tor subunit GluRIIA. They found that such mutants showed greater action potential-evoked presynaptic calcium influx than did mutant flies that lacked GluRIIA and endostatin, which in fact showed wild-type levels of presynaptic calcium influx.
NATURE REVIEWS | NEUROSCIENCE
This suggests that endostatin medi ates presynaptic homeostasis by promoting an above-baseline level of presynaptic calcium entry. This study reveals that Multiplexin has multiple presynaptic functions and that endostatin can act as a transsynaptic signalling molecule that mediates presynaptic homeostasis at the fly NMJ. How endostatin pro motes increased presynaptic calcium influx and the identity of the protease responsible for cleaving Multiplexin and thus regulating endostatin release remain unknown. Darran Yates ORIGINAL RESEARCH PAPER Wang, T. et al. Endostatin is a trans-synaptic signal for homeostatic synaptic plasticity. Neuron http:// dx.doi.org/10.1016/j.neuron.2014.07.003 (2014)
CREATAS
VOLUME 15 | SEPTEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
SYNAPTIC PLASTICITY
A homeostatic messenger mutant flies lacking the endostatin domain showed no defects in baseline synaptic transmission but impaired presynaptic homeostasis
At the fly neuromuscular junction (NMJ), inhibition of postsynaptic glutamate receptors leads to a homeo static rise in presynaptic glutamate release to maintain baseline levels of muscle excitation; however, the identity of the retrograde signal that mediates this effect has been unclear. Now, Davis and colleagues show that a cleavage product of Multiplexin — the fly homologue of mammalian collagen XV and XVIII — can act as a transsynaptic messenger that promotes such homeostatic plasticity. To identify potential media tors of homeostatic plasticity, the authors screened mutated flies for impaired homeostatic presynaptic glutamate release at the NMJ fol lowing philanthotoxin-mediated inhibition of postsynaptic glutamate receptors. They identified two trans poson insertions in Multiplexin that inhibited such release. One of these mutations — dmpf 07253 — was also associated with lower NMJ baseline neurotransmission, suggesting that Multiplexin has at least two separate presynaptic functions. Multiplexin, like its collagen homologues, is composed of mul tiple protein domains, including an amino-terminal thrombospondinlike domain and a carboxyterminal endostatin domain, which is released following proteolytic cleavage. Mutant flies lacking the
thrombospondin-like domain had a decrease in baseline neurotransmis sion at the NMJ but near normal presynaptic homeostasis, whereas mutant flies lacking the endostatin domain showed no defects in baseline synaptic transmission but impaired presynaptic homeostasis. This indicates that the two domains each convey one of the two presynaptic functions of Multiplexin. Collagen XV and XVIII can be found in the extracellular matrix, and the authors found that green fluorescent protein-tagged endostatin could also be found on the surface of neurons and muscles when over expressed in these cells. Moreover, overexpression of endostatin in either the presynaptic neuron or postsyn aptic muscle at the NMJ rescued the homeostatic deficit in dmpf 07253 flies, suggesting that fly endostatin may act as a retrograde signalling molecule. To examine the mechanistic effects of endostatin, the authors used flies that exhibit a persistent homeostatic increase in presynaptic glutamate release owing to deletion of the ionotropic glutamate recep tor subunit GluRIIA. They found that such mutants showed greater action potential-evoked presynaptic calcium influx than did mutant flies that lacked GluRIIA and endostatin, which in fact showed wild-type levels of presynaptic calcium influx.
NATURE REVIEWS | NEUROSCIENCE
This suggests that endostatin medi ates presynaptic homeostasis by promoting an above-baseline level of presynaptic calcium entry. This study reveals that Multiplexin has multiple presynaptic functions and that endostatin can act as a transsynaptic signalling molecule that mediates presynaptic homeostasis at the fly NMJ. How endostatin pro motes increased presynaptic calcium influx and the identity of the protease responsible for cleaving Multiplexin and thus regulating endostatin release remain unknown. Darran Yates ORIGINAL RESEARCH PAPER Wang, T. et al. Endostatin is a trans-synaptic signal for homeostatic synaptic plasticity. Neuron http:// dx.doi.org/10.1016/j.neuron.2014.07.003 (2014)
CREATAS
VOLUME 15 | SEPTEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
