Troy Littleton

#JNeurosci: Findings from Akbergenova, @jtroylittleton.bsky.social et al. provide new insights into how synaptic strength develops as active zones mature, as well as how activity can shape synaptic development.
https://doi.org/10.1523/JNEUROSCI.1143-25.2025

Drosophila community - Monday is the deadline for submitting a student nomination for the Elkins Memorial Lecture at the 2025 CSHL Neurobiology of Drosophila Meeting. It’s a great opportunity to support and recognize our graduate student colleagues in the field! Please spread the word!

Drosophila community friends - please help spread the word for nominations for the Elkins Memorial Lecture at the 2025 Cold Spring Harbor Lab Neurobiology of Drosophila Meeting. It’s a great opportunity to support and recognize our graduate student colleagues in the field!

(8/8) In contrast to silencing, enhanced activity leads to faster material accumulation but also sets an upper limit on AZ size. The study provides new insights into how presynaptic AZ maturation state controls synaptic output and the role activity plays in this process.

(7/8) AZ enlargement following presynaptic silencing requires postsynaptic glutamate receptor-dependent transsynaptic signaling and acts through an independent mechanism from rab3 mutants that also contain larger AZs.

(6/8) The normal process of AZ formation and maturation is altered when action potential generation or SV release is disrupted in individual neurons. Instead of seeding new AZs throughout development, silenced neurons form fewer and larger release sites.

(5/8) In contrast, the abundance of late arriving scaffolding components like RBP, BRP and Unc13A, have a stronger contribution to synaptic efficacy. Maturing AZs that have not yet accumulated Cac channels appear as spontaneous-only release sites that lack evoked fusion.

(4/8) Although early scaffolding components such as Liprin-α and Syd1 arrive first at developing AZs, their overall abundance correlates poorly with Cac Ca2+ channel accumulation and the strength of evoked output at single release sites.

(3/8) Using a new genetic toolkit to time-stamp synapse age, AZ maturation occurs over a multi-day developmental period, with newly formed AZs developing from spontaneous only release sites into high Pr AZs through the coordinated accumulation of a core set of proteins.

(2/8) Yulia’s study follows up on her original synaptic strength heterogeneity work at Drosophila larval NMJs. She finds maturation state of individual AZs defines presynaptic release modes and controls synaptic strength, with activity levels shaping the process.

Active zone maturation state controls synaptic output and release mode and is differentially regulated by neuronal activity Synapse formation requires the gradual accumulation of cytomatrix proteins and voltage-gated Ca2+ channels (VDCCs) at presynaptic active zones (AZs) to support neurotransmitter release. To correlate AZ maturation with synaptic output, quantal imaging was performed at serially imaged time-stamped Drosophila synapses. Evoked release strength correlated strongly with AZ age and accumulation of late AZ scaffolds, while immature sites lacking VDCC accumulation supported spontaneous release. To examine how neuronal activity regulates AZ maturation and protein accumulation, the effects of disruptions to SV fusion or action potential generation were analyzed. Decreasing neuronal activity reduced AZ seeding and caused hyperaccumulation of presynaptic material at existing AZs. Although enlarged AZs are also observed in rab3 mutants, activity reduction acted through an independent mechanism that required postsynaptic glutamate receptor-dependent signaling. Together, these data indicate AZ maturation state sets distinct presynaptic release modes and output strength, with neuronal activity shaping both AZ number and size across development. ### Competing Interest Statement J.M. is an employee of Abberior Instruments America, which commercializes super-resolution microscopy systems, including MINFLUX.

(1/8) New study from Yulia Akbergenova in the lab on how neurons regulate structural and functional maturation of active zones (AZs), a key signaling hub where synaptic communication occurs.

www.biorxiv.org/content/10.1...

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