Homeostatic scaling of active zone scaffolds maintains global synaptic strength

Goel, Pragya; Bergeron, Dominique Dufour; Böhme, Mathias A.; Nunnelly, Luke F.; Lehmann, Martin; Buser, Christopher; Walter, Alexander; Sigrist, Stephan J.; Dickman, Dion

doi:10.1083/jcb.201807165

Cited by 77 publications

(107 citation statements)

References 98 publications

(262 reference statements)

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“…3G). These results parallel recent studies that have shown that while the number and intensity of individual active zones can vary at NMJs, the total abundance of active zone protein remains constant (Goel et al, 2019a; Goel et al, 2019b; Graf et al, 2009). Together, hyper-innervated NMJs express a target-specific reduction in both the number and intensity of release sites and a parallel reduction in presynaptic release probability that stabilizes synaptic strength, while no reciprocal changes are observed at hypo-innervated counterparts.…”

Section: Resultssupporting

confidence: 89%

“…We considered four additional possible mechanisms that could, in principle, contribute to the observed enhancement in quantal size at hypo-innervated NMJs. First, increased presynaptic vesicle size could lead to enhanced glutamate emitted per vesicle, as has been documented in endocytosis mutants and following overexpression of the vesicular glutamate transporter (Daniels et al, 2004; Goel et al, 2019a). Second, multivesicular release has been observed in some systems (Rudolph et al, 2015) and was raised as a possibility in the original study to potentially explain the increased quantal size (Davis and Goodman, 1998), although there remains no evidence for multi-vesicular release at the fly NMJ.…”

Section: Resultsmentioning

confidence: 99%

“…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%

“…Recent studies have shed light on how neurotransmission is stabilized when synaptic growth and function is challenged (Davis and Muller, 2015; Frank et al, 2020; Goel et al, 2019a; Goel et al, 2019b; Li et al, 2018b). However, less is known about how this stability is maintained when neuronal terminals confront diverse and even opposing challenges in synaptic growth and function.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Goel

Nishimura²,

Chetlapalli³

et al. 2020

Preprint

Self Cite

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show abstract

“…Analysis of Syt-GFP puncta in a single brain yielded a value for average puncta number, surface area, and volume ( Figure 3B). In support of this assay, we confirmed that an increase in synaptic contacts can be visualized as a greater number of Syt-GFP puncta: we examined Syt-GFP expression in PI-STAT neurons in which EndophilinA, an endocytic gene previously shown to cause synaptic 25 overgrowth, had been knocked down (STAT-Gal4>UAS-endoA-RNAi), and observed a corresponding increase in Syt-GFP puncta ( Figure S2) (Goel et al, 2019).…”

Section: Establishment Of Presynaptic Bouton Number As a Measurement supporting

confidence: 65%

Adipokines set neural tone by regulating synapse number

Brent

Rajan

2019

Preprint

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Highlights:• The adipokine Upd2 regulates number of inhibitory synaptic contacts on Insulin neurons. 20• Upd2 activates an actin-regulating complex of Arouser, Basigin, and Gelsolin in target neurons.• Arouser, Basigin, and Gelsolin reduce the extent of inhibitory contact on Insulin neurons. 25• Insulin resets negative tone by increasing the number of synaptic contacts made by its own upstream inhibitory neurons. SummaryEnergy sensing neural circuits decide to expend or conserve resources by integrating tonic steady-state energy store information with phasic signals for hunger and food intake. Tonic signals, in the form of adipose tissue-derived adipokines, set the baseline level of energy-sensing neuron activity, providing context for interpretation of phasic messages. However, the mechanism 5 by which tonic adipokine information establishes baseline neuronal function is unclear. Here we show that Upd2, a Drosophila Leptin ortholog, regulates actin-based synapse reorganization by reducing inhibitory synaptic contacts, thereby providing a permissive neural tone for insulin release under conditions of nutrient surplus. Unexpectedly, Insulin acts on the same upstream inhibitory neurons to conversely increase synapse number, hence re-instating negative tone. Our 10 results suggest that two surplus-sensing hormonal systems, Leptin/Upd2 and Insulin, converge on a neuronal circuit with opposing outcomes that establish tonic, energy-store-dependent neuron activity.

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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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Homeostatic scaling of active zone scaffolds maintains global synaptic strength

Cited by 77 publications

References 98 publications

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

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

Adipokines set neural tone by regulating synapse number

Homeostatic control of Drosophila neuromuscular junction function

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