Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles

Wentzel, Corinna; Delvendahl, Igor; Sydlik, Sebastian; Georgiev, Oleg; Müller, Martin

doi:10.1038/s41467-017-02494-0

Cited by 45 publications

(76 citation statements)

References 63 publications

(108 reference statements)

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“…This either 606 favors the hypothesis that acute homeostatic plasticity is accomplished by distinct 607 molecular mechanisms or, in line with the aforementioned findings, is restricted to type 608 Ib terminals. Wentzel et al, 2018 demonstrated that synaptic vesicles recruited from 609 vesicle pools during acute homeostatic plasticity are highly sensitive to EGTA. 610…”

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confidence: 99%

Active zone compaction in presynaptic homeostatic potentiation

Mrestani¹,

Kollmannsberger²,

Pauli³

et al. 2019

Preprint

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19 20 * Correspondence should be adressed to M.H. (heckmann@uni-wuerzburg.de) and 21 M.M.P. (mila.paul@uni-wuerzburg.de) 22molecular environment for fast and precise neurotransmitter release (Kittel et al., 2006; 75 Held and Kaeser, 2018). Whereas the Brp N-term was mapped in membrane-76 proximity, its C-term covers an area of about 0.1 µm 2 , localizes about 155 nm above 77 the postsynaptic receptors (Fouquet et al., 2009; Liu et al., 2011) and is important for 78 tethering of synaptic vesicles (Hallermann et al., 2010). Remarkably, Brp is distributed 79 heterogeneously within the AZ forming about 15 subclusters of 1.6 x 10 -3 µm 2 size 80 (Ehmann et al., 2014). 81 82Alterations in protein number contribute to synaptic differentiation and plasticity. This 83 is well established for receptor channels in postsynaptic densities (Tang et al., 2016). 84Less clear is to what extend presynaptic protein number changes contribute to 85 plasticity. Imaging Brp and other AZ components using confocal and STED microscopy 86 provided evidence for an increase in AZ area and cluster numbers in acute and chronic 87 homeostatic plasticity (Weyhersmüller et al., 2011;Goel et al., 2017; Böhme et al., 88 2019). We suggest that beside an increase in absolute protein numbers per AZ, local 89 protein rearrangements leading to alterations in synaptic strength are conceivable. To 90 address this hypothesis, we performed localization microscopy of AZs in phasic and 91 tonic presynapses at the NMJ and induced presynaptic homeostatic plasticity as a 92 model for acute changes in release (Davis and Müller, 2015). Hierarchical density-93 based spatial clustering (HDBSCAN) enabled unbiased analysis of our datasets. We 94 identified striking differences in AZ scaffold organization with more compact Brp 95 arrangement, increased molecular density and narrower positioning of AZ subclusters 96 in high release probability, phasic type Is boutons compared to low probability, tonic 97 type Ib boutons. Furthermore, we observed similar changes following induction of 98 acute presynaptic plasticity only in tonic type Ib boutons. In summary, our data suggest 99 AZ compaction to be a structural correlate of enhanced synaptic transmission in 100 synaptic differentiation and homeostatic plasticity. 101 5 MATERIAL AND METHODS 102 Fly stocks 103 Flies were raised on standard cornmeal and molasses medium at 25 °C. Drosophila 104 melanogaster wildtype strain w 1118 (Bloomington Drosophila Stock Center) male 3 rd 105 instar larvae were used for experiments. 106 107 Philanthotoxin treatment and and larval preparation 108 Philanthotoxin 433 tris (trifluoroacetate) salt (PhTx, P207 Sigma) was dissolved in 109 dimethyl sulfoxide (DMSO) to obtain a stock solution of 4 mM and stored at -20 °C. For 110 each experiment, the respective volume was further diluted with freshly prepared 111 haemolymph-like solution (HL-3, Stewart et al., 1994) to a final PhTx concentration of 112 20 µM in 0.5 % DMSO. Control experiments were performed with the same DMSO 113 (Dianova)...

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confidence: 99%

Active zone compaction in presynaptic homeostatic potentiation

Mrestani¹,

Kollmannsberger²,

Pauli³

et al. 2019

Preprint

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“…These data suggest that presynaptic proteasomal degradation has the capacity to regulate Ca 2+ influx. Reprinted and adapted from (Wentzel et al, 2018)…”

Section: Physiology and Genesmentioning

confidence: 99%

“…One of the recently discovered genes promoting tight coupling and PHP is fife, a Drosophila Piccolo-RIM homolog (Bruckner et al, 2017; Figure 3a). In addition to tightly-coupled synaptic vesicles, recent experimental evidence suggests a role for "loosely-coupled" vesicles in PHP (Wentzel, Delvendahl, Sydlik, Georgiev, & Müller, 2018).…”

Section: Physiology and Genesmentioning

confidence: 99%

“…Specifically, it was found that release at NMJs undergoing PHP is more sensitive to EGTA-AM, and that EGTA-sensitive vesicles are required for PHP (Wentzel et al, 2018) (but see Genç et al, 2017). This implies that loosely coupled vesicles have to be recruited in addition to tightly coupled vesicles to potentiate release during PHP (see also paragraph "Proteostasis").…”

Section: Physiology and Genesmentioning

confidence: 99%

“…Another related open question concerns the role of synaptic proteostasis during PHP. While impairing the presynaptic UPS blocks PHP (Wentzel et al, 2018), it remains to be determined how the UPS participates in PHP signaling.…”

Section: Open Que S Ti On S and Outlookmentioning

confidence: 99%

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Homeostatic control of Drosophila neuromuscular junction function

Frank

James

Müller

2019

Synapse

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The ability to adapt to changing internal and external conditions is a key feature of biological systems. Homeostasis refers to a regulatory process that stabilizes dynamic systems to counteract perturbations. In the nervous system, homeostatic mechanisms control neuronal excitability, neurotransmitter release, neurotransmitter receptors, and neural circuit function. The neuromuscular junction (NMJ) of Drosophila melanogaster has provided a wealth of molecular information about how synapses implement homeostatic forms of synaptic plasticity, with a focus on the transsynaptic, homeostatic modulation of neurotransmitter release. This review examines some of the recent findings from the Drosophila NMJ and highlights questions the field will ponder in coming years.

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Regulation of synaptic release‐site Ca²⁺ channel coupling as a mechanism to control release probability and short‐term plasticity

2018

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Synaptic transmission relies on the rapid fusion of neurotransmitter-containing synaptic vesicles (SVs), which happens in response to action potential (AP)-induced Ca influx at active zones (AZs). A highly conserved molecular machinery cooperates at SV-release sites to mediate SV plasma membrane attachment and maturation, Ca sensing, and membrane fusion. Despite this high degree of conservation, synapses - even within the same organism, organ or neuron - are highly diverse regarding the probability of APs to trigger SV fusion. Additionally, repetitive activation can lead to either strengthening or weakening of transmission. In this review, we discuss mechanisms controlling release probability and this short-term plasticity. We argue that an important layer of control is exerted by evolutionarily conserved AZ scaffolding proteins, which determine the coupling distance between SV fusion sites and voltage-gated Ca channels (VGCC) and, thereby, shape synapse-specific input/output behaviors. We propose that AZ-scaffold modifications may occur to adapt the coupling distance during synapse maturation and plastic regulation of synapse strength.

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Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles

Cited by 45 publications

References 63 publications

Active zone compaction in presynaptic homeostatic potentiation

Active zone compaction in presynaptic homeostatic potentiation

Homeostatic control of Drosophila neuromuscular junction function

Regulation of synaptic release‐site Ca²⁺ channel coupling as a mechanism to control release probability and short‐term plasticity

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Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles

Cited by 45 publications

References 63 publications

Active zone compaction in presynaptic homeostatic potentiation

Active zone compaction in presynaptic homeostatic potentiation

Homeostatic control of Drosophila neuromuscular junction function

Regulation of synaptic release‐site Ca2+ channel coupling as a mechanism to control release probability and short‐term plasticity

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Regulation of synaptic release‐site Ca²⁺ channel coupling as a mechanism to control release probability and short‐term plasticity