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Synaptic neurexin-1 assembles into dynamically regulated active zone nanoclusters.

Justin H Trotter1,2, Junjie Hao3,4,5, Stephan Maxeiner1,2

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Neurexins, crucial presynaptic cell adhesion molecules, form discrete nanoclusters at excitatory synapses. Their synaptic levels are dynamically regulated by ADAM10 cleavage, impacting synapse organization.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Synaptic Plasticity

Background:

  • Neurexins are presynaptic cell adhesion molecules vital for synapse function.
  • Their precise synaptic localization and regulation have remained unclear.

Purpose of the Study:

  • To investigate the synaptic localization and organization of neurexins.
  • To explore the role of ectodomain cleavage in neurexin regulation.

Main Methods:

  • Super-resolution microscopy to visualize neurexin nanoclusters.
  • Biochemical assays to assess protein cleavage.
  • Pharmacological inhibition of ADAM10 protease.

Main Results:

  • Neurexin-1 forms discrete nanoclusters at excitatory synapses, co-localizing with other neurexin isoforms.
  • Neurexin-1 and neuroligin-1 are physiologically cleaved by ADAM10.
  • Inhibition of ADAM10 cleavage significantly increases synaptic neurexin-1 content and nanocluster formation.

Conclusions:

  • Synapses exhibit a novel nanodomain organization involving neurexin-1 nanoclusters.
  • ADAM10-mediated ectodomain cleavage dynamically regulates synaptic neurexin levels and organization.