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J Neurosci. 2019 Mar 22. pii: 2601-18. doi: 10.1523/JNEUROSCI.2601-18.2019. [Epub ahead of print]

A screen for synaptic growth mutants reveals mechanisms that stabilize synaptic strength.

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Department of Neurobiology.
USC Graduate Program in Molecular and Computational Biology.
USC Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA.
Department of Neurobiology


Synapses grow, prune, and remodel throughout development, experience, and disease. This structural plasticity can destabilize information transfer in the nervous system. However, neural activity remains remarkably stable throughout life, implying adaptive countermeasures exist that maintain neurotransmission within proper physiological ranges. Aberrant synaptic structure and function has been associated with a variety of neural diseases including Fragile X syndrome, autism, and intellectual disability. We have screened 300 mutants in Drosophila larvae of both sexes for defects in synaptic growth at the neuromuscular junction, identifying 12 mutants with severe reductions or enhancements in synaptic growth. Remarkably, electrophysiological recordings revealed synaptic strength was unchanged in all but one of these mutants compared to wild type. We utilized a combination of genetic, anatomical, and electrophysiological analyses to illuminate three mechanisms that stabilize synaptic strength despite major disparities in synaptic growth. These include compensatory changes in 1) postsynaptic neurotransmitter receptor abundance; 2) presynaptic morphology; and 3) active zone structure. Together, this characterization identifies new mutants with defects in synaptic growth and the adaptive strategies employed by synapses to homeostatically stabilize neurotransmission in response.SIGNIFICANCE STATEMENTThis study reveals compensatory mechanisms employed by synapses to ensure stable functionality during severe alterations in synaptic growth using the neuromuscular junction of Drosophila melanogaster as a model system. Through a forward genetic screen, we identify mutants that exhibit dramatic under- or over-grown synapses yet express stable levels of synaptic strength, with three specific compensatory mechanisms discovered. Thus, this study reveals novel insights into the adaptive strategies that constrain neurotransmission within narrow physiological ranges while allowing considerable flexibility in overall synapse number. More broadly, these findings provide insights into how stable synaptic function may be maintained in the nervous system during periods of intensive synaptic growth, pruning, and remodeling.

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