Rapid active zone remodeling consolidates presynaptic potentiation

Böhme, Mathias A.; McCarthy, Anthony W.; Grasskamp, Andreas T.; Beuschel, Christine B.; Goel, Pragya; Jusyte, Meida; Laber, Desiree; Huang, Sheng; Rey, Ulises; Petzoldt, Astrid G.; Lehmann, Martin; Göttfert, Fabian; Haghighi, Pejmun; Hell, Stefan W.; Owald, David; Dickman, Dion; Sigrist, Stephan J.; Walter, Alexander

doi:10.1038/s41467-019-08977-6

Cited by 104 publications

(126 citation statements)

References 90 publications

(132 reference statements)

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“…Interestingly, also in Drosophila activity-dependent modulations of the active zone of photoreceptor synapses were observed 94 . The molecular composition of the active zone is crucial for presynaptic signaling 1,95 . The molecular mechanisms of how the ribbon contributes to the darkness-induced increased recruitment of Cav1.4 and RIM2 to the active zone remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

Dembla

Maxeiner

et al. 2020

Sci Rep

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Rod photoreceptor synapses use large, ribbon-type active zones for continuous synaptic transmission during light and dark. Since ribbons are physically connected to the active zones, we asked whether illumination-dependent changes of ribbons influence Cav1.4/RIM2 protein clusters at the active zone and whether these illumination-dependent effects at the active zone require the presence of the synaptic ribbon. We found that synaptic ribbon length and the length of presynaptic Cav1.4/RIM2 clusters are tightly correlated. Dark-adaptation did not change the number of ribbons and active zone puncta. However, mean ribbon length and length of presynaptic Cav1.4/RIM2 clusters increased significantly during dark-adaptation when tonic exocytosis is highest. In the present study, we identified by the analyses of synaptic ribbon-deficient RIBEYE knockout mice that synaptic ribbons are (1) needed to stabilize Cav1.4/RIM2 at rod photoreceptor active zones and (2) are required for the darkness-induced active zone enrichment of Cav1.4/RIM2. These data propose a role of the ribbon in active zone stabilization and suggest a homeostatic function of the ribbon in illumination-dependent active zone remodeling. The active zone of the presynaptic terminal controls central aspects of presynaptic communication 1,2. It is a protein-rich, electron-dense specialization of the plasma membrane at which synaptic vesicle fusion preferentially occurs. The active zone is strongly enriched in voltage-gated Cav-channels and active zone proteins, e.g. RIM-proteins, that attach the vesicle fusion machinery in close proximity to the Cav-channels for tight coupling creating rapidly reacting nanodomains 1,3-9. Ribbon synapses are continuously active chemical synapses with specialized active zones that are considered to promote both fast, transient and slow, continuous synaptic vesicle exocytosis 10,11. The active zone of ribbon synapses is extended by large electron-dense structures, synaptic ribbons, that recruit additional vesicles to the active zone. The basal row of ribbon-associated vesicles is positioned close to the Cav-channels and represents the fastest releasable vesicle pool 12 ideally suited to signal the onset of a stimulus. Synaptic vesicles tethered to the ribbon body, i.e. in some distance from the active zone, are considered to replenish empty release sites at the active zone with slower release kinetics providing information predominantly about the length of the stimulus 12,13. The main structural component of ribbons is the ribbon-specific protein RIBEYE 14,15. Photoreceptor ribbon synapses are the first synapses in the visual system at which light signals are transmitted to the inner retina. Light induces hyperpolarization of photoreceptors and a decrease of exocytosis at the synapse 16. Rod synapses represent the majority of photoreceptor synapses in the mouse retina and are built in a morphologically fairly uniform manner. They use a single large active zone with a single large ribbon. In EM cross-sections, rod ribbons typically ap...

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Section: Discussionmentioning

confidence: 99%

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

Dembla

Maxeiner

et al. 2020

Sci Rep

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“…At the Drosophila NMJ, there is considerable heterogeneity in the size and intensity of the active zone scaffold BRP and other active zone components (Guerrero et al, 2005;Peled and Isacoff, 2011;Ehmann et al, 2014;Akbergenova et al, 2018;Gratz et al, 2019). Furthermore, recent studies have shown that increasing intensity and size of active zone components, including BRP, Unc13, and the Ca 2ϩ channel Cac, predict increased release probability during baseline transmission and after homeostatic plasticity (Weyhersmüller et al, 2011;Goel et al, 2017Goel et al, , 2019bLi et al, 2018a;Böhme et al, 2019;Gratz et al, 2019). We therefore considered that while the total number of BRP puncta per NMJ was increased in the overgrowth mutants, there might have been a corresponding change in the area and/or intensity of each puncta that contributed to their modulation of release probability.…”

Section: Reduced Active Zone Area In Synaptic Overgrowth Mutants Compmentioning

confidence: 99%

“…Indeed, a positive correlation between the size and intensity of active zone components and release probability has been demonstrated at the Drosophila NMJ (Guerrero et al, 2005;Peled and Isacoff, 2011;Akbergenova et al, 2018) as well as at mammalian central synapses (Murthy et al, 2001;Matz et al, 2010;Holderith et al, 2012;Glebov et al, 2017). Furthermore, BRP can be remodeled during presynaptic homeostatic potentiation to enhance release probability at active zones (Weyhersmüller et al, 2011;Goel et al, 2017Goel et al, , 2019bBöhme et al, 2019;Gratz et al, 2019). Therefore, the reduction in active zone size observed in the overgrowth mutants likely reduces release probability at individual release sites to maintain global neurotransmitter output at the NMJ, an adaptation most dramatically illustrated in endophilin mutants (Goel et al, 2019b).…”

Section: Homeostatic Scaling Of Glutamate Receptor Abundance and Actimentioning

confidence: 99%

A Screen for Synaptic Growth Mutants Reveals Mechanisms That Stabilize Synaptic Strength

et al. 2019

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Synapses grow, prune, and remodel throughout development, experience, and disease. This structural plasticity can destabilize information transfer in the nervous system. However, neural activity remains stable throughout life, implying that adaptive countermeasures exist that maintain neurotransmission within proper physiological ranges. Aberrant synaptic structure and function have been associated with a variety of neural diseases, including Fragile X syndrome, autism, and intellectual disability. We have screened 300 mutants in Drosophila larvae of both sexes for defects in synaptic growth at the neuromuscular junction, identifying 12 mutants with severe reductions or enhancements in synaptic growth. Remarkably, electrophysiological recordings revealed that synaptic strength was unchanged in all but one of these mutants compared with WT. We used a combination of genetic, anatomical, and electrophysiological analyses to illuminate three mechanisms that stabilize synaptic strength despite major disparities in synaptic growth. These include compensatory changes in (1) postsynaptic neurotransmitter receptor abundance, (2) presynaptic morphology, and (3) active zone structure. Together, this characterization identifies new mutants with defects in synaptic growth and the adaptive strategies used by synapses to homeostatically stabilize neurotransmission in response.This study reveals compensatory mechanisms used by synapses to ensure stable functionality during severe alterations in synaptic growth using the neuromuscular junction of Drosophila melanogaster as a model system. Through a forward genetic screen, we identify mutants that exhibit dramatic undergrown or overgrown synapses yet express stable levels of synaptic strength, with three specific compensatory mechanisms discovered. Thus, this study reveals novel insights into the adaptive strategies that constrain neurotransmission within narrow physiological ranges while allowing considerable flexibility in overall synapse number. More broadly, these findings provide insights into how stable synaptic function may be maintained in the nervous system during periods of intensive synaptic growth, pruning, and remodeling.

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“…In principle, a target-specific reduction in the number and/or function of anatomical release sites could explain these electrophysiological properties. In addition, recent evidence indicates that bi-directional changes in the size and nano-structure of active zone architecture at Drosophila NMJs can adjust release probability at individual active zones (Akbergenova et al, 2018; Bohme et al, 2019; Goel et al, 2019a; Gratz et al, 2019). We therefore characterized the number and intensity of individual active zones on hyper-innervated NMJs by immunostaining the central scaffold BRP and endogenously tagged CaV2.1 calcium channels [Cac sfGFP ; (Gratz et al, 2019)], defining each BRP punctum to be an active zone.…”

Section: Resultsmentioning

confidence: 99%

Distinct target-specific mechanisms homeostatically stabilize transmission at pre-and post-synaptic compartments

Goel

Nishimura²,

Chetlapalli³

et al. 2020

Preprint

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27Neurons must establish and stabilize connections made with diverse targets, each with distinct 28 demands and functional characteristics. At Drosophila neuromuscular junctions, synaptic 29 strength remains stable in a manipulation that simultaneously induces hypo-innervation on one 30 target and hyper-innervation on the other. However, the expression mechanisms that achieve 31 this exquisite target-specific homeostatic control remain enigmatic. Here, we identify the distinct 32 target-specific homeostatic expression mechanisms. On the hypo-innervated target, an increase 33 in postsynaptic glutamate receptor (GluR) abundance is sufficient to compensate for reduced 34 innervation, without any apparent presynaptic adaptations. In contrast, a target-specific 35 reduction in presynaptic neurotransmitter release probability is reflected by a decrease in active 36 zone components restricted to terminals of hyper-innervated targets. Finally, loss of 37 postsynaptic GluRs on one target induces a compartmentalized, homeostatic enhancement of 38 presynaptic neurotransmitter release called presynaptic homeostatic potentiation that can be 39 precisely balanced with the adaptations required for both hypo-and hyper-innervation to 40 maintain stable synaptic strength. Thus, distinct anterograde and retrograde signaling systems 41 operate at pre-and post-synaptic compartments to enable target-specific, homeostatic control of 42 neurotransmission. 43 44 45 46 47 48 49 50 51 52 3 INTRODUCTION 53Synapses are spectacularly diverse in their morphology, physiology, and functional 54 characteristics. These differences are reflected in the molecular composition and abundance of 55 synaptic components at heterogenous synaptic subtypes in central and peripheral nervous 56 systems (Atwood and Karunanithi, 2002; Branco and Staras, 2009; O'Rourke et al., 2012). 57Interestingly, the structure and function of synapses can also vary substantially across terminals 58 of an individual neuron (Fekete et al., 2019; Grillo et al., 2018; Guerrero et al., 2005) and drive 59 input-specific presynaptic plasticity (Letellier et al., 2019). Both Hebbian and homeostatic 60 plasticity mechanisms can work locally and globally at specific synapses to tune synapse 61 function, enabling stable yet flexible ranges of synaptic strength (Diering and Huganir, 2018; 62 Turrigiano, 2012; Vitureira and Goda, 2013). For example, homeostatic receptor scaling globally 63 adjusts GluR abundance, subtype, and/or functionality at dendrites (Turrigiano and Nelson, 642004) yet there is also evidence for synapse specificity (Béïque et al., 2011; Hou et al., 2008; 65 Sutton et al., 2006). Although a number of studies have begun to elucidate the factors that 66 enable both local and global modes of synaptic plasticity at synaptic compartments, it is less 67 appreciated how and why specific synapses undergo plasticity within the context and needs of 68 information transfer in a neural circuit. 69One major force that sculpts the heterogeneity of synaptic strength is impose...

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Rapid active zone remodeling consolidates presynaptic potentiation

Cited by 104 publications

References 90 publications

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

Synaptic ribbons foster active zone stability and illumination-dependent active zone enrichment of RIM2 and Cav1.4 in photoreceptor synapses

A Screen for Synaptic Growth Mutants Reveals Mechanisms That Stabilize Synaptic Strength

Distinct target-specific mechanisms homeostatically stabilize transmission at pre-and post-synaptic compartments

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