(M)Unc13s in Active Zone Diversity: A Drosophila Perspective

Abstract

The so-called active zones at pre-synaptic terminals are the ultimate filtering devices, which couple between action potential frequency and shape, and the information transferred to the post-synaptic neurons, finally tuning behaviors. Within active zones, the release of the synaptic vesicle operates from specialized “release sites.” The (M)Unc13 class of proteins is meant to define release sites topologically and biochemically, and diversity between Unc13-type release factor isoforms is suspected to steer diversity at active zones. The two major Unc13-type isoforms, namely, Unc13A and Unc13B, have recently been described from the molecular to the behavioral level, exploiting Drosophila being uniquely suited to causally link between these levels. The exact nanoscale distribution of voltage-gated Ca2+ channels relative to release sites (“coupling”) at pre-synaptic active zones fundamentally steers the release of the synaptic vesicle. Unc13A and B were found to be either tightly or loosely coupled across Drosophila synapses. In this review, we reported recent findings on diverse aspects of Drosophila Unc13A and B, importantly, their nano-topological distribution at active zones and their roles in release site generation, active zone assembly, and pre-synaptic homeostatic plasticity. We compared their stoichiometric composition at different synapse types, reviewing the correlation between nanoscale distribution of these two isoforms and release physiology and, finally, discuss how isoform-specific release components might drive the functional heterogeneity of synapses and encode discrete behavior.

Endogenous tagging of Unc-13 reveals nanoscale reorganization at active zones during presynaptic homeostatic potentiation

“…This finding matches the heterogeneity of synaptic release and, as the amount of other crucial AZ components like Brp seems to correlate with the amount of evoked release, creating release maps of Unc-13 GFSTF can be an appealing experimental approach to clarify the functional relevance of distinct nano-arrangements ( Peled et al, 2014 ; Akbergenova et al, 2018 ; Newman et al, 2022 ). In this study, we tagged both Unc-13 isoforms Unc-13A and Unc-13B, however, different expression patterns and roles in AZ assembly have been described for these isoforms ( Piao and Sigrist, 2022 ). Relating isoform-specific Unc-13 imaging and our findings is attractive but beyond the scope of this manuscript.…”

“…Furthermore, the N-terminus of Unc-13A in Drosophila is essential for presynaptic homeostatic potentiation (PHP, Böhme et al, 2019 ). Two Unc-13 isoforms in Drosophila , Unc-13A and Unc-13B, play different roles in release coupling and their localization at presynaptic AZs was studied using no longer available, subtype-specific antibodies ( Piao and Sigrist, 2022 ). We decided to study the nano-topology of all Unc-13 isoforms at the Drosophila neuromuscular junction (NMJ) to analyze the general expression pattern of this important release site marker.…”

A brain-wide form of presynaptic active zone plasticity orchestrates resilience to brain aging in Drosophila

“…Our previous study described a new form of global presynaptic active zone plasticity upon early Drosophila aging (Gupta et al, 2016), which here we refer to as PreScale. It is characterized by a brain-wide increase in the ELKS-family core active zone scaffold protein Bruchpilot (BRP) and BRP-associated release factors, particularly (m)Unc13-family protein Unc13A which is crucial for SV release at Drosophila synapses (Kittel et al, 2006; Wagh et al, 2006; Böhme et al, 2016; Gupta et al, 2016; Piao and Sigrist, 2022). Notably, BRP seems to operate as a master scaffold of the Drosophila active zone which recruits a spectrum of synaptic proteins to tune presynaptic active zone composition and consequently drives synaptic plasticity (Fouquet et al, 2009; Huang et al, 2020; Huang and Sigrist, 2020).…”

Synapse Dysfunctions in Multiple Sclerosis

“…Active zone proteins recruit the vesicle fusion/priming machinery near voltage-gated Cav channels [ 111 , 112 ]. The distance between Cav channels and the vesicle release machinery is relevant for synaptic vesicle release probability [ 113 ]. Different types of voltage-gated Ca 2+ channels endow the synapse with characteristic signaling properties [ 114 , 115 ].…”