Interplay between hevin, SPARC, and MDGAs: Modulators of neurexin-neuroligin transsynaptic bridges

Fan, Shanghua; Gangwar, S.P.; Machius, Mischa; Rudenko, Gabby

doi:10.1016/j.str.2021.01.003

Cited by 18 publications

(34 citation statements)

References 74 publications

(122 reference statements)

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“…Indeed, MDGA1 transcripts were recently found to be regulated in response to chronic synaptic activity blockade ( Silva et al, 2019 ). Moreover, the action of MDGAs might be finely tuned by other proteins associated to the NRXN-NLGN trans-synaptic complex, including hevin and SPARC that are secreted by astrocytes ( Fan et al, 2021 ). Interestingly, the presence of NLGNs in astrocytes offers an additional level of regulation of synapse development through such a network of proteins ( Stogsdill et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior

Toledo

Letellier

Bimbi

et al. 2022

eLife

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MDGA molecules can bind neuroligins and interfere with trans-synaptic interactions to neurexins, thereby impairing synapse development. However, the subcellular localization and dynamics of MDGAs, or their specific action mode in neurons remain unclear. Here, surface immunostaining of endogenous MDGAs and single molecule tracking of recombinant MDGAs in dissociated hippocampal neurons reveal that MDGAs are homogeneously distributed and exhibit fast membrane diffusion, with a small reduction in mobility across neuronal maturation. Knocking-down/out MDGAs using shRNAs and CRISPR/Cas9 strategies increases the density of excitatory synapses, the membrane confinement of neuroligin-1, and the phosphotyrosine level of neuroligins associated with excitatory post-synaptic differentiation. Finally, MDGA silencing reduces the mobility of AMPA receptors, increases the frequency of miniature EPSCs (but not IPSCs), and selectively enhances evoked AMPA-receptor-mediated EPSCs in CA1 pyramidal neurons. Overall, our results support a mechanism by which interactions between MDGAs and neuroligin-1 delays the assembly of functional excitatory synapses containing AMPA receptors.

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Section: Discussionmentioning

confidence: 99%

MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior

Toledo

Letellier

Bimbi

et al. 2022

eLife

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“…Indeed, MDGA1 transcripts were recently found to be upregulated in response to chronic synaptic activity blockade 57 . Moreover, the action of MDGAs might be finely tuned by other proteins associated to the NRXN-NLGN trans-synaptic complex, including hevin and SPARC that are secreted by astrocytes 58 . Interestingly, the presence of NLGNs in astrocytes offers an additional level of regulation of synapse development through such a network of proteins 59 .…”

Section: Discussionmentioning

confidence: 99%

MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior

Toledo

Bimbi

Letellier

et al. 2021

Preprint

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MDGAs are molecules that can bind neuroligins in cis and interfere with trans-synaptic neurexin-neuroligin interactions, thereby impairing synapse development. However, the sub-cellular localization and dynamics of MDGAs, as well as their specific mode of action in neurons are still unclear. Here, using both surface immunostaining of endogenous MDGAs and single molecule tracking of recombinant MDGAs in dissociated hippocampal neurons, we show that MDGA1 and MDGA2 molecules are homogeneously distributed and exhibit fast membrane diffusion, with a small reduction in mobility across neuronal maturation in culture Using shRNAs and CRISPR/Cas9 strategies to knock-down/out MDGA1 or MDGA2, we demonstrate an increase in the density of excitatory synapses accompanied by enhanced membrane immobilization and an increase in the phosphotyrosine level of neuroligins associated with excitatory post-synaptic differentiation. Finally, we show that decreasing MDGA expression level reduces the mobility of AMPA receptors and increases the frequency of AMPA receptor mediated mEPSCs. Overall, our results support a mechanism by which interactions between MDGAs and neuroligin-1 delays the assembly of functional excitatory synapses containing AMPA receptors.

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“…Astrocytes promote synaptogenesis by releasing various molecules, such as brain-derived neurotrophic factor, hevin, thrombospondin, and TGF-β [ 83 ]. Hevin, for example, stabilizes the connection of the two trans-synaptic adhesion molecules neurexin and neuroligin [ 84 ]. Moreover, astrocytes contribute to the stabilization of AMPA receptors at the post-synapse, thereby promoting synaptic maturation [ 83 ].…”

Section: Astrocytes In Health and Diseasementioning

confidence: 99%

Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

Heider

Vogel

Volkmer

et al. 2021

IJMS

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Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.

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Interplay between hevin, SPARC, and MDGAs: Modulators of neurexin-neuroligin transsynaptic bridges

Cited by 18 publications

References 74 publications

MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior

MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior

MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior

Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

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