Homeostatic synaptic scaling: molecular regulators of synaptic AMPA-type glutamate receptors

Chowdhury, Dhrubajyoti; Hell, Johannes

doi:10.12688/f1000research.13561.1

Cited by 45 publications

(41 citation statements)

References 80 publications

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“…This phenomenon parallels homeostatic scaling of postsynaptic glutamate receptors following manipulations to activity in mammalian central neurons (Turrigiano et al, 1998;Aoto et al, 2008;Turrigiano, 2008;Chen et al, 2014). While glutamate receptors are dynamically regulated in central neurons during both Hebbian and homeostatic forms of plasticity (Pérez-Otaño and Ehlers, 2005;Herring and Nicoll, 2016;Chowdhury and Hell, 2018), receptors at the NMJ are much less dynamic. Glutamate receptors have half-lives of ϳ24 h at the Drosophila NMJ , similar to the relatively slow turnover of cholinergic receptors at the mammalian NMJ (Salpeter and Harris, 1983).…”

Section: Homeostatic Scaling Of Glutamate Receptor Abundance and Actimentioning

confidence: 78%

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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Section: Homeostatic Scaling Of Glutamate Receptor Abundance and Actimentioning

confidence: 78%

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

et al. 2019

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“…On the hypo-innervated target, a selective upregulation in postsynaptic GluR abundance was elicited that was sufficient in magnitude to offset reduced neurotransmitter release and stabilize synaptic strength. This scaling of GluR abundance parallels a well-established mechanism of homeostatic synaptic plasticity in mammalian neurons termed homeostatic receptor scaling (Chowdhury and Hell, 2018; Diering and Huganir, 2018; Turrigiano, 2008). Although an enhanced upregulation of GluRs occurs in response to reduced activity in mammalian central neurons, the GluR scaling revealed at the fly NMJ is unique.…”

Section: Discussionmentioning

confidence: 66%

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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“…This phenomenon parallels homeostatic receptor scaling of postsynaptic glutamate receptors following manipulations to activity in mammalian central neurons [94-97]. While glutamate receptors are rapidly and dynamically regulated in central neurons during both Hebbian and homeostatic forms of plasticity [10, 98, 99], receptors at the NMJ are much less dynamic. Glutamate receptors have half lifes of ~24 hr at the Drosophila NMJ [100], which parallels the relatively slow dynamics of cholinergic receptors at the mammalian NMJ [101].…”

Section: Discussionmentioning

confidence: 91%

A screen for genes that regulate synaptic growth reveals mechanisms that stabilize synaptic strength

Goel

Khan

Howard

et al. 2018

Preprint

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23 24 25 26 2 ABSTRACT 27Synapses grow, prune, and remodel throughout development, experience, and disease. This 28 structural plasticity can destabilize information transfer in the nervous system. However, neural 29 activity remains remarkably stable throughout life, implying that adaptive countermeasures exist 30 to stabilize neurotransmission. Aberrant synaptic structure and function has been associated 31 with a variety of neural diseases including Fragile X syndrome, autism, and intellectual disability. 32We have screened disruptions in over 300 genes in Drosophila for defects in synaptic growth at 33 the neuromuscular junction. This effort identified 12 mutants with severe reductions or 34 enhancements in synaptic growth. Remarkably, electrophysiological recordings revealed 35 synaptic strength in all but one of these mutants was unchanged compared to wild type. We 36 utilized a combination of genetic, anatomical, and electrophysiological analyses to illuminate 37 three mechanisms that stabilize synaptic strength in the face of alterations in synaptic growth. 38These include compensatory changes in 1) postsynaptic receptor abundance; 2) presynaptic 39 morphology; and 3) active zone structure. Together, this analysis identifies new genes that 40 regulate synaptic growth and the adaptive strategies that synapses employ to homeostatically 41 stabilize synaptic strength in response. 42 43 44 45 46 47 48 49 50 51 52 3 AUTHOR SUMMARY 53Throughout development, maturation, experience, and disease, synapses undergo dramatic 54 changes in growth and remodeling. Although these processes are necessary for learning and 55 memory, they pose major challenges to stable function in the nervous system. However, 56 neurotransmission is typically constrained within narrow physiological ranges, implying the 57 existence of homeostatic mechanisms that maintain stable functionality despite drastic 58 alterations in synapse number. In this study we investigate the relationship between synaptic 59 growth and function across a variety of mutations in neural and synaptic genes in the fruitfly 60 Drosophila melanogaster. Using the neuromuscular junction as a model system, we reveal three 61 adaptive mechanisms that stabilize synaptic strength when synapses are dramatically under-or 62 over-grown. Together, these findings provide insights into the strategies employed at both pre-63 and post-synaptic compartments to ensure stable functionality while allowing considerable 64 flexibility in overall synapse number. 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79Dramatic changes in synapse number, morphology, and structure occur throughout nervous 80 system development and during various forms of plasticity and remodeling in the mature 81 nervous system. For example, expansion and retraction of synaptic terminals contributes to the 82 refinement of neural circuits during developmental pruning, sleep/wake behavior, and 83 experience-dependent plasticity [1][2][3][4]. While these dynamic changes enable the flexibility 84 necessary to wire the ne...

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Homeostatic synaptic scaling: molecular regulators of synaptic AMPA-type glutamate receptors

Cited by 45 publications

References 80 publications

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

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

A screen for genes that regulate synaptic growth reveals mechanisms that stabilize synaptic strength

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