Secreted tissue inhibitor of matrix metalloproteinase restricts <i>trans</i>-synaptic signaling to coordinate synaptogenesis

Shilts, Jarrod; Broadie, Kendal

doi:10.1242/jcs.200808

Cited by 17 publications

(12 citation statements)

References 110 publications

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“…We further suggest that the synaptic co-localization of Dlp and Mmp1 is mediated through Dlp HS-GAG chains, with Dlp recruiting essential Mmp1 function driving activity-dependent bouton formation. With in situ zymography proteolytic function tests at the synapse (33, 88), we consistently found that reduced Mmp function correlated with Dlp depletion and increased function with Dlp overexpression. However, enzymatic activity appears primarily dependent upon interaction with the Dlp core protein.…”

Section: Discussionmentioning

confidence: 71%

“…4, 5), we next assayed whether these changes correlate with synaptic proteolytic activity. We used in situ zymography at the NMJ to measure the metalloproteinase-dependent conversion of a dye-quenched fluorogenic gelatin (DQ-gelatin), and quantified fluorescence changes in both the dlp reduction and overexpression conditions used above (33, 88). Although this method cannot differentiate the contributions of different proteases, it provides a live readout of net enzymatic activity through quantifiable fluorescence changes.…”

Section: Resultsmentioning

confidence: 99%

“…NMJ in situ zymography assays were performed as previously described (33, 88). Briefly, live larval preparations were dissected exposing the neuromusculature in physiological saline, and then immediately submerged in the zymography buffer (50 mM Tris-HCl, 150 mM NaCl, 5 mM CaCl 2 , 0.2 mM NaN 3 , pH 7.6) containing 500 μg/ml of fluorescein-conjugate DQ porcine gelatin (Molecular Probes by Life Technologies, D-12054).…”

Section: Methodsmentioning

confidence: 99%

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Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

2017

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Matrix metalloproteinase (MMP) functions modulate synapse formation and activity-dependent plasticity, with MMP dysfunction implicated in Fragile X syndrome (FXS), a disease caused by the loss of the RNA binding protein FMRP and characterized by neurological dysfunction and intellectual disability. Gene expression studies in Drosophila suggest that Mmps cooperate with the heparan sulfate proteoglycan (HSPG) glypican co-receptor Dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling, and that synaptogenic defects in the fly model of FXS are alleviated by both Mmp inhibition and Dlp genetic reduction. Here, we used the Drosophila neuromuscular junction (NMJ) glutamatergic synapse to test activity-dependent Dlp and Mmp intersections in the context of FXS. We found that rapid, activity-dependent synaptic bouton formation was dependent upon secreted Mmp1. Acute neuronal stimulation reduced Mmp2 abundance, but increased that of both Mmp1 and Dlp as well as Dlp and Mmp1 co-localization at the synapse. Dlp function bidirectionally controlled Mmp1 abundance, localization and proteolytic activity around synapses. Dlp glycosaminoglycan (GAG) chains mediated this functional interaction with Mmp1. In the FXS fly model, activity-dependent increases in Mmp1 abundance and activity were lost but were restored by reducing the amount of synaptic Dlp. These data indicate that neuronal activity-induced, HSPG-dependent Mmp regulation drives activity-dependent synaptogenesis, and that this is impaired in FXS. Thus exploring this mechanism further may reveal therapeutic targets with potential to restore synaptogenesis in FXS patients.

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Section: Discussionmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

2017

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“…MMP-9 could be released from excitatory inputs to PV expressing neurons. Indeed, MMPs have been noted at synaptic boutons (Shilts and Broadie, 2017).…”

Section: Discussionmentioning

confidence: 99%

Venlafaxine stimulates an MMP-9-dependent increase in excitatory/inhibitory balance in a stress model of depression

Alaiyed

McCann

Mahajan

et al. 2019

Preprint

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AbstractEmerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts approximately 14-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, and may diminish excitatory neurotransmission. Enhanced deposition of perineuronal net (PNN) components also occurs with stress. Since parvalbumin-expressing interneurons are the predominant cell population that is enveloped by PNNs, which enhance their ability to release GABA, excess PNN deposition likely increases pyramidal cell inhibition. In the present study we investigate the potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of venlafaxine, a serotonin/norepinephrine reuptake inhibitor. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in the cortex of wild-type but not MMP-9 null mice. We have previously shown that venlafaxine reduces PNN deposition and increases the power of ex vivo gamma oscillations in conventionally-housed mice. Gamma power is increased with pyramidal cell disinhibition and with remission from MDD. Herein we observe that PNN expression is increased in a corticosterone-induced stress model of disease and reduced by venlafaxine. As compared to mice that receive concurrent venlafaxine, corticosterone treated mice also display reduced ex vivo gamma power and impaired working memory. Autopsy-derived prefrontal cortex samples show elevated MMP-9 levels in anti-depressant treated MDD patients as compared to controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD.

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“…It remains unclear how octopamine signaling at type I synaptic regions regulates postsynaptic Dlp levels. Broadie and collaborators revealed that ECM metalloproteinases (Mmp1 and Mmp2) and the tissue inhibitor of metalloproteinases (Timp) play critical roles in synapse formation and activity-dependent plasticity in the Drosophila NMJ (Dear et al, 2016(Dear et al, , 2017Shilts and Broadie, 2017). Mmp2 from the presynaptic and postsynaptic compartments has been shown to negatively regulate synaptic Dlp levels at the NMJ, possibly by the proteolytic cleavage of Dlp core proteins (Wang and Page-McCaw, 2014).…”

Section: Discussionmentioning

confidence: 99%

The HSPG Glypican Regulates Experience-Dependent Synaptic and Behavioral Plasticity by Modulating the Non-Canonical BMP Pathway

et al. 2019

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Graphical Abstract Highlights d Octopaminergic signaling regulates postsynaptic Dlp levels during starvation d dlp is required for starvation-induced synaptic growth and locomotor behavior d Dlp regulates GluRIIA-mediated non-canonical BMP signaling d This BMP signaling regulates starvation-induced behavioral and synaptic plasticities SUMMARYUnder food deprivation conditions, Drosophila larvae exhibit increases in locomotor speed and synaptic bouton numbers at neuromuscular junctions (NMJs). Octopamine, the invertebrate counterpart of noradrenaline, plays critical roles in this process; however, the underlying mechanisms remain unclear. We show here that a glypican (Dlp) negatively regulates type I synaptic bouton formation, postsynaptic expression of GluRIIA, and larval locomotor speed. Starvation-induced octopaminergic signaling decreases Dlp expression, leading to increases in synapse formation and locomotion. Dlp is expressed by postsynaptic muscle cells and suppresses the non-canonical BMP pathway, which is composed of the presynaptic BMP receptor Wit and postsynaptic GluRIIA-containing ionotropic glutamate receptor. We find that during starvation, decreases in Dlp increase non-canonical BMP signaling, leading to increases in GluRIIA expression, type I bouton number, and locomotor speed. Our results demonstrate that octopamine controls starvation-induced neural plasticity by regulating Dlp and provides insights into how proteoglycans can influence behavioral and synaptic plasticity.

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Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

Cited by 17 publications

References 110 publications

Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis

Venlafaxine stimulates an MMP-9-dependent increase in excitatory/inhibitory balance in a stress model of depression

The HSPG Glypican Regulates Experience-Dependent Synaptic and Behavioral Plasticity by Modulating the Non-Canonical BMP Pathway

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