Distinct molecular pathways govern presynaptic homeostatic plasticity

Nair, Archana Padmanabhan; Muttathukunnel, Paola; Müller, Martin

doi:10.1016/j.celrep.2021.110105

Cited by 12 publications

(7 citation statements)

References 71 publications

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“…Electrophysiology data were acquired with Clampex (Molecular Devices) and analyzed using routines written with scientific python libraries, including numpy, scipy, IPython, and neo ( 43 ). mEPSPs were detected using an implementation of a template-matching algorithm ( 44 , 45 ). Quantal content was calculated as the ratio between the mean EPSP amplitude and the mean mEPSP amplitude for each cell.…”

Section: Methodsmentioning

confidence: 99%

Rapid homeostatic modulation of transsynaptic nanocolumn rings

Muttathukunnel

Frei

Perry

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific arrangement of proteins within presynaptic active zones. How the specific presynaptic molecular architecture relates to postsynaptic organization and how synaptic nano-architecture is transsynaptically regulated to enable stable synaptic transmission remain enigmatic. Using time-gated stimulated emission-depletion microscopy at the Drosophila neuromuscular junction, we found that presynaptic nanorings formed by the active-zone scaffold Bruchpilot (Brp) align with postsynaptic glutamate receptor (GluR) rings. Individual rings harbor approximately four transsynaptically aligned Brp-GluR nanocolumns. Similar nanocolumn rings are formed by the presynaptic protein Unc13A and GluRs. Intriguingly, acute GluR impairment triggers transsynaptic nanocolumn formation on the minute timescale during homeostatic plasticity. We reveal distinct phases of structural transsynaptic homeostatic plasticity, with postsynaptic GluR reorganization preceding presynaptic Brp modulation. Finally, homeostatic control of transsynaptic nano-architecture and neurotransmitter release requires the auxiliary GluR subunit Neto. Thus, transsynaptic nanocolumn rings provide a substrate for rapid homeostatic stabilization of synaptic efficacy.

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Section: Methodsmentioning

confidence: 99%

Rapid homeostatic modulation of transsynaptic nanocolumn rings

Muttathukunnel

Frei

Perry

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent characterization of motor neuron-specific tools allow a refinement of analyses, at least in the context of presynaptic terminals (Han et al, 2022, Aponte-Santiago et al, 2020, Wang et al, 2021). For a second model, a recent study suggests that the type of pharmacological perturbation to glutamate receptors might control the eventual response (Nair et al, 2021). A third model is that short-term and long-term events that stabilize the NMJ are governed by genetically separable signaling systems (Brusich et al, 2015, James et al, 2019, Spring et al, 2016, Yeates et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Acute induction occurs rapidly in minutes (Frank et al, 2006), while chronic maintenance occurs over an extended developmental time (Davis et al, 1998, DiAntonio et al, 1999, Petersen et al, 1997). Acute PHP can be induced and expressed by applying glutamate receptor inhibitors, like Philanthotoxin-433 (PhTx) (Frank et al, 2006) or GYKI-53655 (Nair et al, 2021). For chronic PHP expression, glutamate receptors can be homeostatically challenged genetically using a loss of function mutation in GluRIIA SP16 (Petersen et al, 1997), RNAi-mediated knockdown of GluRIII RNAi (Brusich et al, 2015), or a variety of other genetic manipulations that impair glutamate receptor expression throughout development (reviewed in (Frank, 2014)).…”

Section: Introductionmentioning

confidence: 99%

The calcineurin regulator Sarah enables distinct forms of homeostatic plasticity at theDrosophilaneuromuscular junction

Armstrong

Frank

2022

Preprint

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The ability of synapses to maintain physiological levels of evoked neurotransmission is essential for neuronal stability. A variety of perturbations can disrupt neurotransmission, but synapses often compensate for disruptions and work to stabilize activity levels, using forms of homeostatic synaptic plasticity. Presynaptic homeostatic potentiation (PHP) is one such mechanism that is expressed at the model Drosophila melanogaster larval neuromuscular junction (NMJ) synapse. In PHP, neurotransmitter release increases in response to challenges to the synapse, resulting in the maintenance of evoked neurotransmission. Prior work separated PHP into two temporal phases, acute and chronic. Those data suggested that cytoplasmic calcium signaling was important for a long-term maintenance of PHP. Here we used a combination of transgenic Drosophila RNA interference and overexpression lines, along with NMJ electrophysiology, synapse imaging, and pharmacology to test if regulators of the calcium/calmodulin-dependent protein phosphatase calcineurin are necessary for the normal expression of acute or chronic forms of PHP. We found that either pre- or postsynaptic dysregulation of a Drosophila gene regulating calcineurin, sarah (sra), blocks PHP. Examination of tissue-specific data showed that increases and decreases in sra expression are both detrimental to PHP. Additionally, the acute and chronic phases of PHP are functionally separable depending entirely upon which sra genetic manipulation is used. Surprisingly, concurrent pre- and postsynaptic sra knockdown or overexpression ameliorated PHP blocks revealed in single tissue experiments. Pharmacological inhibition of calcineurin corroborated this latter finding. Our results suggest that a discrete balance of calcineurin signaling is needed across multiple synapse tissue types and over different temporal phases to stabilize peripheral synaptic outputs.

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“…Recent characterization of motor neuron-specific tools allows refinement of analyses, at least in the context of presynaptic terminals (Aponte-santiago et al, 2020 ; Wang et al, 2021 ; Han et al, 2022 ). For a second model, a recent study suggests that the type of pharmacological perturbation to glutamate receptors might control the eventual response (Nair et al, 2021 ). A third model is that short-term and long-term events that stabilize the NMJ are governed by genetically separable signaling systems (Brusich et al, 2015 ; Spring et al, 2016 ; Yeates et al, 2017 ; James et al, 2019 ).…”

Section: Models Of Compensation: Pharmacology Vs Genetics Spatial Vs ...mentioning

confidence: 99%

“…By contrast, genetic manipulations last over extended developmental time (Petersen et al, 1997 ; Davis et al, 1998 ; Diantonio et al, 1999 ). Acute PHP can be induced and expressed by applying glutamate receptor inhibitors, like Philanthotoxin-433 (PhTx; Frank et al, 2006 ) or GYKI-53655 (Nair et al, 2021 ). Alternatively, glutamate receptors can be impaired genetically using a loss of function mutation in GluRIIA SP16 (Petersen et al, 1997 ), RNAi-mediated knockdown of GluRIII (Brusich et al, 2015 ), or a variety of other manipulations that impair receptor expression throughout development (reviewed in Frank, 2014a ).…”

Section: Introductionmentioning

confidence: 99%

The calcineurin regulator Sarah enables distinct forms of homeostatic plasticity at the Drosophila neuromuscular junction

Armstrong

Frank

2023

Front. Synaptic Neurosci.

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Introduction: The ability of synapses to maintain physiological levels of evoked neurotransmission is essential for neuronal stability. A variety of perturbations can disrupt neurotransmission, but synapses often compensate for disruptions and work to stabilize activity levels, using forms of homeostatic synaptic plasticity. Presynaptic homeostatic potentiation (PHP) is one such mechanism. PHP is expressed at the Drosophila melanogaster larval neuromuscular junction (NMJ) synapse, as well as other NMJs. In PHP, presynaptic neurotransmitter release increases to offset the effects of impairing muscle transmitter receptors. Prior Drosophila work has studied PHP using different ways to perturb muscle receptor function—either acutely (using pharmacology) or chronically (using genetics). Some of our prior data suggested that cytoplasmic calcium signaling was important for expression of PHP after genetic impairment of glutamate receptors. Here we followed up on that observation.Methods: We used a combination of transgenic Drosophila RNA interference and overexpression lines, along with NMJ electrophysiology, synapse imaging, and pharmacology to test if regulators of the calcium/calmodulin-dependent protein phosphatase calcineurin are necessary for the normal expression of PHP.Results: We found that either pre- or postsynaptic dysregulation of a Drosophila gene regulating calcineurin, sarah (sra), blocks PHP. Tissue-specific manipulations showed that either increases or decreases in sra expression are detrimental to PHP. Additionally, pharmacologically and genetically induced forms of expression of PHP are functionally separable depending entirely upon which sra genetic manipulation is used. Surprisingly, dual-tissue pre- and postsynaptic sra knockdown or overexpression can ameliorate PHP blocks revealed in single-tissue experiments. Pharmacological and genetic inhibition of calcineurin corroborated this latter finding.Discussion: Our results suggest tight calcineurin regulation is needed across multiple tissue types to stabilize peripheral synaptic outputs.

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Distinct molecular pathways govern presynaptic homeostatic plasticity

Cited by 12 publications

References 71 publications

Rapid homeostatic modulation of transsynaptic nanocolumn rings

Rapid homeostatic modulation of transsynaptic nanocolumn rings

The calcineurin regulator Sarah enables distinct forms of homeostatic plasticity at theDrosophilaneuromuscular junction

The calcineurin regulator Sarah enables distinct forms of homeostatic plasticity at the Drosophila neuromuscular junction

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