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Target-dependent retrograde signaling mediates synaptic plasticity at the Drosophila neuromuscular junction.

ABSTRACT: Neurons that innervate multiple targets often establish synapses with target-specific strengths, and local forms of synaptic plasticity. We have examined the molecular-genetic mechanisms that allow a single Drosophila motoneuron, the ventral Common Exciter (vCE), to establish connections with target-specific properties at its various synaptic partners. By driving transgenes in a subset of vCE's targets, we found that individual target cells are able to independently control the properties of vCE's innervating branch and synapses. This is achieved by means of a trans-synaptic growth factor secreted by the target cell. At the larval neuromuscular junction, postsynaptic glutamate receptor activity stimulates the release of the BMP4/5/6 homolog Glass bottom boat (Gbb). As larvae mature and motoneuron terminals grow, Gbb activates the R-Smad transcriptional regulator phosphorylated Mad (pMad) to facilitate presynaptic development. We found that manipulations affecting glutamate receptors or Gbb within subsets of target muscles led to local effects either specific to the manipulated muscle or by a limited gradient within the presynaptic branches. While presynaptic development depends on pMad transcriptional activity within the motoneuron nucleus, we find that the Gbb growth factor may also act locally within presynaptic terminals. Local Gbb signaling and presynaptic pMad accumulation within boutons may therefore participate in a "synaptic tagging" mechanism, to influence synaptic growth and plasticity in Drosophila.

SUBMITTER: Berke B

PROVIDER: S-EPMC7397725 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Target-dependent retrograde signaling mediates synaptic plasticity at the Drosophila neuromuscular junction.

Berke Brett B Le Linh L Keshishian Haig H

Developmental neurobiology 20191101 11-12

Neurons that innervate multiple targets often establish synapses with target-specific strengths, and local forms of synaptic plasticity. We have examined the molecular-genetic mechanisms that allow a single Drosophila motoneuron, the ventral Common Exciter (vCE), to establish connections with target-specific properties at its various synaptic partners. By driving transgenes in a subset of vCE's targets, we found that individual target cells are able to independently control the properties of vCE ...[more]

PMID: 31950660

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Project description:Forms of homeostatic plasticity stabilize neuronal outputs and promote physiologically favorable synapse function. A well-studied homeostatic system operates at the Drosophila melanogaster larval neuromuscular junction (NMJ). At the NMJ, impairment of postsynaptic glutamate receptor activity is offset by a compensatory increase in presynaptic neurotransmitter release. We aim to elucidate how this process operates on a molecular level and is preserved throughout development. In this study, we identified a tyrosine kinase-driven signaling system that sustains homeostatic control of NMJ function. We identified C-terminal Src Kinase (Csk) as a potential regulator of synaptic homeostasis through an RNAi- and electrophysiology-based genetic screen. We found that Csk loss-of-function mutations impaired the sustained expression of homeostatic plasticity at the NMJ, without drastically altering synapse growth or baseline neurotransmission. Muscle-specific overexpression of Src Family Kinase (SFK) substrates that are negatively regulated by Csk also impaired NMJ homeostasis. Surprisingly, we found that transgenic Csk-YFP can support homeostatic plasticity at the NMJ when expressed either in the muscle or in the nerve. However, only muscle-expressed Csk-YFP was able to localize to NMJ structures. By immunostaining, we found that Csk mutant NMJs had dysregulated expression of the Neural Cell Adhesion Molecule homolog Fasciclin II (FasII). By immunoblotting, we found that levels of a specific isoform of FasII were decreased in homeostatically challenged GluRIIA mutant animals-but markedly increased in Csk mutant animals. Additionally, we found that postsynaptic overexpression of FasII from its endogenous locus was sufficient to impair synaptic homeostasis, and genetically reducing FasII levels in Csk mutants fully restored synaptic homeostasis. Based on these data, we propose that Csk and its SFK substrates impinge upon homeostatic control of NMJ function by regulating downstream expression or localization of FasII.

Dataset Information

Target-dependent retrograde signaling mediates synaptic plasticity at the Drosophila neuromuscular junction.

Publications

Target-dependent retrograde signaling mediates synaptic plasticity at the Drosophila neuromuscular junction.

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