An active zone state switch concentrates and immobilizes voltage-gated Ca2+ channels to promote long-term plasticity

Ghelani, Tina; Escher, Marc; Thomas, Ulrike; Esch, Klara; Lützkendorf, Janine; Depner, Harald; Maglione, Marta; Parutto, Pierre; Gratz, Scott J.; Ryglewski, Stefanie; Walter, Alexander; Holcman, David; O’Connor-Giles, Kate M.; Heisenberg, Martin; Sigrist, Stephan J.

doi:10.21203/rs.3.rs-1292687/v1

Cited by 4 publications

(10 citation statements)

References 35 publications

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“…This compaction of AZ structure does appear capable of enhancing neurotransmitter release, as a similar compaction has been reported for Ib AZs following a form of adaptive plasticity known as presynaptic homeostatic potentiation (PHP) (Dannhäuser et al, 2022; Goel & Dickman, 2021; Mrestani et al, 2021). Furthermore, an intriguing recent study added an additional layer of regulation of Cac at AZs, where the nanoscale mobility and localization within individual MN-Ib AZs was subject to dynamic regulation at basal and plasticity states (Ghelani et al, 2022). Although these dynamics were not studied at MN-Is AZs, distinctions in Cac mobility and dynamics likely also contribute to the functional differences in tonic vs phasic release sites.…”

Section: Discussionmentioning

confidence: 99%

“…What mechanism(s) might be responsible for the two-fold higher Ca 2+ influx per action potential at MN-Is release sites over -Ib? While the abundance of Ca V 2 Ca 2+ channels at AZs can increase in the context of presynaptic plasticity (Cao & Tsien, 2010;Ghelani et al, 2022;Goel, Bergeron, et al, 2019;Gratz et al, 2019;Sheng et al, 2012), distinctions in Cac abundance do not appear to explain the differences in Ca 2+ influx at tonic vs phasic release sites. Instead, we consider several possibilities that are not mutually exclusive.…”

Section: Presynaptic Release Properties Of Mn-is Vs -Ibmentioning

confidence: 99%

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Physiologic and nanoscale distinctions define glutamatergic synapses in tonic vs phasic neurons

Han

et al. 2022

Preprint

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Neurons exhibit a striking degree of functional diversity, each one tuned to the needs of the circuitry in which it is embedded. A fundamental functional dichotomy occurs in activity patterns, with some neurons firing at a relatively constant “tonic” rate, while others fire in bursts - a “phasic” pattern. Synapses formed by tonic vs phasic neurons are also functionally differentiated, yet the bases of their distinctive properties remain enigmatic. A major challenge towards illuminating the synaptic differences between tonic and phasic neurons is the difficulty in isolating their physiological properties. At theDrosophilaneuromuscular junction (NMJ), most muscle fibers are co-innervated by two motor neurons, the tonic “MN-Ib” and phasic “MN-Is”. Here, we employed selective expression of a newly developed botulinum neurotoxin (BoNT-C) transgene to silence tonic or phasic motor neurons. This approach revealed major differences in their neurotransmitter release properties, including probability, short-term plasticity, and vesicle pools. Furthermore, Ca2+imaging demonstrated ~two-fold greater Ca2+influx at phasic neuron release sites relative to tonic, along with enhanced synaptic vesicle coupling. Finally, confocal and super resolution imaging revealed that phasic neuron release sites are organized in a more compact arrangement, with enhanced stoichiometry of voltage-gated Ca2+channels relative to other active zone scaffolds. These data suggest that distinctions in active zone nano-architecture and Ca2+influx collaborate to differentially tune glutamate release at synapses of tonic vs phasic neuronal subtypes.

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Section: Discussionmentioning

confidence: 99%

Section: Presynaptic Release Properties Of Mn-is Vs -Ibmentioning

confidence: 99%

Physiologic and nanoscale distinctions define glutamatergic synapses in tonic vs phasic neurons

Han

et al. 2022

Preprint

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“…Additionally, RIM interacts stoichiometrically with Ca v 2 (Kaeser et al, 2011;Oh et al, 2021). However, in mammalian central synapses and Drosophila NMJs, loss of RIM and RBP binding to the C-terminal of VGCCs did not reduce channel AZ localization (Schneider et al, 2015;Lübbert et al, 2017;Ghelani et al, 2022). Indeed, several studies reported the lack of RIM and RBP interactions actually promotes channel stability at AZs, opposite to what would be expected for a protein functioning as a VGCC slot interactor (Schneider et al, 2015;Ghelani et al, 2022).…”

Section: The Slot Model For Vgcc Accumulation At Azsmentioning

confidence: 94%

“…The conserved AZ scaffold proteins are attractive candidates for locally mediating slots at the AZ. Drosophila BRP is well situated to be a slot protein, as it binds directly to the Ca v 2 channel and is required for channel accumulation and stabilization at AZs (Fouquet et al, 2009;Ghelani et al, 2022). However, reductions in AZ BRP abundance have no effect on AZ VGCC levels, indicating this protein is likely not a ratelimiting regulator of VGCCs at AZs (Cunningham et al, 2022).…”

Section: The Slot Model For Vgcc Accumulation At Azsmentioning

confidence: 99%

“…Next, we focus on the channel's mobility once incorporated into AZs. Despite binding to multiple scaffolds, single-molecule tracking studies indicate VGCCs are highly mobile within the AZ (Mercer et al, 2011(Mercer et al, , 2012Thoreson et al, 2013;Schneider et al, 2015;Voigt et al, 2016;Ghelani et al, 2022). In addition to VGCC mobility, we review molecular pathways facilitating endocytosis, although limited in situ information is available to contextualize these molecular pathways in intact circuits.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms controlling the trafficking, localization, and abundance of presynaptic Ca2+ channels

Cunningham

Littleton

2023

Front. Mol. Neurosci.

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Voltage-gated Ca2+ channels (VGCCs) mediate Ca2+ influx to trigger neurotransmitter release at specialized presynaptic sites termed active zones (AZs). The abundance of VGCCs at AZs regulates neurotransmitter release probability (Pr), a key presynaptic determinant of synaptic strength. Given this functional significance, defining the processes that cooperate to establish AZ VGCC abundance is critical for understanding how these mechanisms set synaptic strength and how they might be regulated to control presynaptic plasticity. VGCC abundance at AZs involves multiple steps, including channel biosynthesis (transcription, translation, and trafficking through the endomembrane system), forward axonal trafficking and delivery to synaptic terminals, incorporation and retention at presynaptic sites, and protein recycling. Here we discuss mechanisms that control VGCC abundance at synapses, highlighting findings from invertebrate and vertebrate models.

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Role of α2δ-3 in regulating calcium channel localization at presynaptic active zones during homeostatic plasticity

Zhang,

Wang,

Cai

et al. 2023

Front. Mol. Neurosci.

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The homeostatic modulation of synaptic transmission is an evolutionarily conserved mechanism that is critical for stabilizing the nervous system. At the Drosophila neuromuscular junction (NMJ), presynaptic homeostatic potentiation (PHP) compensates for impairments in postsynaptic glutamate receptors due to pharmacological blockade or genetic deletion. During PHP, there is an increase in presynaptic neurotransmitter release, counteracting postsynaptic changes and restoring excitation to baseline levels. Previous studies have shown that α2δ-3, an auxiliary subunit of voltage-gated calcium channels (VGCCs), is essential for both the rapid induction and sustained expression of PHP at the Drosophila NMJ. However, the molecular mechanisms by which α2δ-3 regulates neurotransmitter release during PHP remain to be elucidated. In this study, we utilized electrophysiological, confocal imaging, and super-resolution imaging approaches to explore how α2δ-3 regulates synaptic transmission during PHP. Our findings suggest that α2δ-3 governs PHP by controlling the localization of the calcium channel pore-forming α1 subunit at presynaptic release sites, or active zones. Moreover, we examined the role of two structural domains within α2δ-3 in regulating neurotransmitter release and calcium channel localization. Our results highlight that these domains in α2δ-3 serve distinct functions in controlling synaptic transmission and presynaptic calcium channel abundance, at baseline in the absence of perturbations and during PHP. In summary, our research offers compelling evidence that α2δ-3 is an indispensable signaling component for controlling calcium channel trafficking and stabilization in homeostatic plasticity.

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An active zone state switch concentrates and immobilizes voltage-gated Ca2+ channels to promote long-term plasticity

Cited by 4 publications

References 35 publications

Physiologic and nanoscale distinctions define glutamatergic synapses in tonic vs phasic neurons

Physiologic and nanoscale distinctions define glutamatergic synapses in tonic vs phasic neurons

Mechanisms controlling the trafficking, localization, and abundance of presynaptic Ca2+ channels

Role of α2δ-3 in regulating calcium channel localization at presynaptic active zones during homeostatic plasticity

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