Current molecular approaches to investigate pre-synaptic dysfunction

J Neurochem. 2021 Apr;157(2):107-129. doi: 10.1111/jnc.15316. Epub 2021 Mar 16.


Over the course of the last few decades it has become clear that many neurodevelopmental and neurodegenerative disorders have a synaptic defect, which contributes to pathogenicity. A rise in new techniques, and in particular '-omics'-based methods providing large datasets, has led to an increase in potential proteins and pathways implicated in synaptic function and related disorders. Additionally, advancements in imaging techniques have led to the recent discovery of alternative modes of synaptic vesicle recycling. This has resulted in a lack of clarity over the precise role of different pathways in maintaining synaptic function and whether these new pathways are dysfunctional in neurodevelopmental and neurodegenerative disorders. A greater understanding of the molecular detail of pre-synaptic function in health and disease is key to targeting new proteins and pathways for novel treatments and the variety of new techniques currently available provides an ideal opportunity to investigate these functions. This review focuses on techniques to interrogate pre-synaptic function, concentrating mainly on synaptic vesicle recycling. It further examines techniques to determine the underlying molecular mechanism of pre-synaptic dysfunction and discusses methods to identify molecular targets, along with protein-protein interactions and cellular localization. In combination, these techniques will provide an expanding and more complete picture of pre-synaptic function. With the application of recent technological advances, we are able to resolve events with higher spatial and temporal resolution, leading research towards a greater understanding of dysfunction at the presynapse and the role it plays in pathogenicity.

Keywords: electron microscopy; live cell imaging; presynapse; super-resolution; synaptic vesicle; synaptopathy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Exocytosis / physiology*
  • Humans
  • Microscopy, Electron / methods
  • Neurodegenerative Diseases / metabolism
  • Synapses / metabolism*
  • Synaptic Transmission / physiology*
  • Synaptic Vesicles / metabolism*