C-terminal Src Kinase Gates Homeostatic Synaptic Plasticity and Regulates Fasciclin II Expression at the Drosophila Neuromuscular Junction

Ashlyn M Spring; Douglas J Brusich; C Andrew Frank

doi:10.1371/journal.pgen.1005886

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C-terminal Src Kinase Gates Homeostatic Synaptic Plasticity and Regulates Fasciclin II Expression at the Drosophila Neuromuscular Junction

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C-terminal Src Kinase Gates Homeostatic Synaptic Plasticity and Regulates Fasciclin II Expression at the Drosophila Neuromuscular Junction

Ashlyn M Spring, Douglas J Brusich and C Andrew Frank

PLoS genetics, Vol.12(2), pp.e1005886-e1005886

02/2016

DOI: 10.1371/journal.pgen.1005886

PMCID: PMC4764653

PMID: 26901416

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Abstract

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.

Animals, Genetically Modified

Neuromuscular Junction - metabolism

CSK Tyrosine-Protein Kinase

Homeostasis

Drosophila Proteins - metabolism

Mutation - genetics

Synaptic Transmission

Drosophila melanogaster - metabolism

Animals

Protein Isoforms - metabolism

Neuronal Plasticity

src-Family Kinases - metabolism

Neuroglia - metabolism

Cell Adhesion Molecules, Neuronal - metabolism

Drosophila Proteins - genetics

src-Family Kinases - genetics

Details

Title: Subtitle: C-terminal Src Kinase Gates Homeostatic Synaptic Plasticity and Regulates Fasciclin II Expression at the Drosophila Neuromuscular Junction
Creators: Ashlyn M Spring - Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa, United States of America
Douglas J Brusich - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
C Andrew Frank - Interdisciplinary Programs in Genetics, Neuroscience, and MCB, University of Iowa, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.12(2), pp.e1005886-e1005886
DOI: 10.1371/journal.pgen.1005886
PMID: 26901416
PMCID: PMC4764653
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: Public Library Science; United States
Grant note: T32 GM008629 / NIGMS NIH HHS NS062738 / NINDS NIH HHS R00 NS062738 / NINDS NIH HHS T32GM008629 / NIGMS NIH HHS K99 NS062738 / NINDS NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Anatomy and Cell Biology; Iowa Neuroscience Institute
Record Identifier: 9984025349802771

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