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Active Zone Maturation Controls Presynaptic Output and Release Mode and Is Regulated by Neuronal Activity.

Yulia Akbergenova1,2, Jessica Matthias3, Sofya Makeyeva4,2

  • 1Departments of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 yulakb@mit.edu troy@mit.edu.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|October 14, 2025
PubMed
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Synapse maturation involves protein accumulation at active zones (AZs). Neuronal activity shapes AZ development, influencing synaptic efficacy and neurotransmitter release across synapse development.

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DrosophilaNMJactive zoneneurotransmitter releasesynapsesynaptic vesicle fusion

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Developmental Biology

Background:

  • Synapse formation requires presynaptic active zone (AZ) maturation, involving the ordered assembly of cytomatrix proteins and voltage-gated calcium channels (VGCCs).
  • The Drosophila melanogaster larval neuromuscular junction serves as a model to study the dynamic processes of AZ maturation and its functional consequences.

Purpose of the Study:

  • To investigate how active zone (AZ) maturation regulates presynaptic output and neurotransmitter release.
  • To determine the role of neuronal activity in regulating AZ maturation, including scaffold protein incorporation and turnover.

Main Methods:

  • Serial imaging of AZ formation and function in time-stamped Drosophila larval neuromuscular junctions.
  • Utilized photoconvertible proteins (mMaple, BRP, Unc13B, Unc13A) for tracking protein dynamics and localization.
  • Performed quantal imaging and analyzed the effects of disrupted neurotransmitter release and genetic mutations (rab3) on AZ development.

Main Results:

  • Older, more mature synapses exhibit higher synaptic efficacy and sustained neurotransmitter release compared to immature synapses.
  • Reduced neuronal activity decreased AZ seeding, increased material accumulation at existing AZs, and reduced scaffold protein turnover.
  • Activity reduction impacted both early (Unc13B) and late (Unc13A) scaffold seeding through a mechanism independent of Rab3 but dependent on postsynaptic signaling.

Conclusions:

  • Active zone maturation is a key regulator of presynaptic release mode and output strength during synapse development.
  • Neuronal activity actively shapes both the number and size of active zones throughout development, influencing synapse function.
  • Activity-dependent regulation of AZ maturation involves distinct mechanisms controlling scaffold incorporation and protein turnover.