Presynaptic DLG regulates synaptic function through the localization of voltage-activated Ca2+ Channels

Astorga, César; Jorquera, Ramón A.; Ramírez, M Simón; Kohler, Andrés; López, Estefanía; Delgado, Ricardo; Córdova, Andrés; Olguı́n, Patricio; Sierralta, Jimena

doi:10.1038/srep32132

Cited by 16 publications

(30 citation statements)

References 44 publications

(70 reference statements)

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“…In the future it will be interesting to examine how Tnc/integrin complexes engage the spectrin-based lattice. Candidate intermediates include actin filaments or Dlg/MAGUK isoforms which could both bind integrin and cluster presynaptic voltage-gated Ca 2+ channels (Astorga et al, 2016;Beumer et al, 2002;Guzman et al, 2019;Ruiz-Canada and Budnik, 2006). Integrin activation generally promotes formation of focal adhesion complexes and cell migration.…”

Section: Discussionmentioning

confidence: 99%

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

Wang

Friend

Vicidomini

et al. 2019

Preprint

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We have previously reported that Drosophila Tenectin (Tnc) recruits PS2/PS integrin to ensure structural and functional integrity at larval NMJs (Wang et al., 2018). In muscles, Tnc/integrin engages the spectrin network to regulate the size and architecture of synaptic boutons. In neurons, Tnc/integrin controls neurotransmitter release. Here we show that presynaptic Tnc/integrin modulates the synaptic accumulation of key active zone components, including the Ca 2+ channel Cac and the active zone scaffold Brp. Presynaptic α-Spectrin appears to be both required and sufficient for the recruitment of Cac and Brp. We visualized the endogenous α-Spectrin and found that Tnc controls spectrin recruitment at synaptic terminals. Thus, Tnc/integrin anchors the presynaptic spectrin network and ensures the proper assembly and function of the active zones. Since pre-and postsynaptic Tnc/integrin limit each other, we hypothesize that this pathway links dynamic changes within the synaptic cleft to changes in synaptic structure and function. The synaptic extracellular matrix (ECM) contains various synaptic organizers and diffusible molecules that establish and modify synaptic connections during development. ECM receptors, including integrins, transduce these signals by sensing the changes in the synaptic environment and orchestrating the appropriate changes in synapse structure and function (Chavis and Westbrook, 2001;Huang et al., 2006). Disruption of integrins impair synapse development and maturation, neurotransmission, and long-term synaptic plasticity (reviewed in (Park and Goda, 2016)). Integrins together with their ECM ligands form complexes with cytoskeletal proteins and active zone (AZ) components (Carlson et al., 2010;Nishimune et al., 2004;Sunderland et al., 2000). However, it remains unclear how these interactions could influence neurotransmitter release.Spectrin, a principal component of the membrane skeleton, is critical for synaptic transmission (Featherstone et al., 2001;Goodman, 1999). Spectrin subunits function as docking platforms for membrane channels, neurotransmitter receptors and adhesion molecules (reviewed in (Machnicka et al., 2014)). For example, spectrins associate with presynaptic Ca 2+ channels in synaptosome lysates (Carlson et al., 2010;Khanna et al., 2007a;Khanna et al., 2007b). Also, a spectrin-containing presynaptic web enables AZ function in the rodent CNS (Phillips et al., 2001). Recent super-resolution fluorescence microscopy uncovered periodic actin/spectrin lattices along axons, dendrites and spines in a broad range of neuronal cell types (He et al., 2016;Qu et al., 2017;Xu et al., 2013); however, at presynaptic and postsynaptic sites, these patterns were absent (Sidenstein et al., 2016).We have previously found that Drosophila Tenectin (Tnc), an integrin ligand that accumulates in the synaptic cleft at the larval NMJ, modulates synapse development and function (Wang et al., 2018). Tnc recruits αPS2/βPS integrin and forms cis active complexes with distinct pre-and post-synaptic functions....

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Section: Discussionmentioning

confidence: 99%

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

Wang

Friend

Vicidomini

et al. 2019

Preprint

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“…A-C). Thus, down-regulation of either of these genes does not significantly alter the overall Bruchpilot and Synaptotagmin 1 levels over the KC synapses, even if all the three proteins have been described as present in the axonal compartment of neurons (Torroja et al, 1996, Astorga et al, 2016, Chen and Featherstone, 2011. Thus, the memory defect observed previously cannot be directly linked to gross deficit in the synaptic vesicle or active zone organization but likely rely on more subtle mechanisms, as for example decreased plasticity of only a confined subset of synapses after knockdown of APPL/CASK.…”

Section: Downregulation Of Appl and Its Synaptic Maguks Partners In Tmentioning

confidence: 98%

“…CASK and Dlg, the Drosophila homologs of the identified mammalian interactants of APP, are expressed at the synapse and involved in synaptic plasticity, just like their mammalian counterparts (Hodge et al, 2006;Astorga et al, 2016;Oliva et al, 2012). However, their role in appetitive olfactory memory has never been determined.…”

Section: Expression Of Maguks In the Adult Mb Is Required For Appetitmentioning

confidence: 99%

Interactions between amyloid precursor protein-like (APPL) and MAGUK scaffolding proteins contribute to appetitive long-term memory inDrosophila melanogaster

Silva

Niehage

Maglione

et al. 2020

Journal of Neurogenetics

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Amyloid precursor protein (APP), the precursor of amyloid beta peptide, plays a central role in Alzheimer's disease (AD), a pathology characterized by memory decline and synaptic loss upon aging. Understanding the physiological role of APP is fundamental in deciphering the progression of AD, and several studies suggest a synaptic function via protein-protein interactions. Nevertheless, it remains unclear whether and how these interactions contribute to memory. In Drosophila, we previously showed that APP-like (APPL), the fly APP homolog, is required for aversive associative memory in the olfactory memory center, the mushroom body (MB). In the present study, we show that APPL is required for appetitive long-term memory (LTM), another form of associative memory, in a specific neuronal subpopulation of the MB, the a'/b' Kenyon cells. Using a biochemical approach, we identify the synaptic MAGUK (membrane-associated guanylate kinase) proteins X11, CASK, Dlgh2 and Dlgh4 as interactants of the APP intracellular domain (AICD). Next, we show that the Drosophila homologs CASK and Dlg are also required for appetitive LTM in the a'/b' neurons. Finally, using a double RNAi approach, we demonstrate that genetic interactions between APPL and CASK, as well as between APPL and Dlg, are critical for appetitive LTM. In summary, our results suggest that APPL contributes to associative long-term memory through its interactions with the main synaptic scaffolding proteins CASK and Dlg. This function should be conserved across species.

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“…Some factors traditionally associated with chiefly pre or postsynaptic roles including Dlg and Liprin-α, also display opposite localization albeit at a reduced abundance, suggesting the need to reconsider these factors for in new contexts. Dlg presents a presynaptic pool similar to Liprin-α which has been shown to promote the AZ localization of Cac, with effects on synaptic release probability and short-term plasticity [236]. Liprin-α, which has been chiefly studied as a presynaptic AZ protein, displays an overwhelmingly postsynaptic distribution [121,156].…”

Section: The Postsynaptic Cytomatrixmentioning

confidence: 99%

Synapse development and maturation at the drosophila neuromuscular junction

2020

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Synapses are the sites of neuron-to-neuron communication and form the basis of the neural circuits that underlie all animal cognition and behavior. Chemical synapses are specialized asymmetric junctions between a presynaptic neuron and a postsynaptic target that form through a series of diverse cellular and subcellular events under the control of complex signaling networks. Once established, the synapse facilitates neurotransmission by mediating the organization and fusion of synaptic vesicles and must also retain the ability to undergo plastic changes. In recent years, synaptic genes have been implicated in a wide array of neurodevelopmental disorders; the individual and societal burdens imposed by these disorders, as well as the lack of effective therapies, motivates continued work on fundamental synapse biology. The properties and functions of the nervous system are remarkably conserved across animal phyla, and many insights into the synapses of the vertebrate central nervous system have been derived from studies of invertebrate models. A prominent model synapse is the Drosophila melanogaster larval neuromuscular junction, which bears striking similarities to the glutamatergic synapses of the vertebrate brain and spine; further advantages include the simplicity and experimental versatility of the fly, as well as its century-long history as a model organism. Here, we survey findings on the major events in synaptogenesis, including target specification, morphogenesis, and the assembly and maturation of synaptic specializations, with a emphasis on work conducted at the Drosophila neuromuscular junction.

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Presynaptic DLG regulates synaptic function through the localization of voltage-activated Ca2+ Channels

Cited by 16 publications

References 44 publications

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

Interactions between amyloid precursor protein-like (APPL) and MAGUK scaffolding proteins contribute to appetitive long-term memory inDrosophila melanogaster

Synapse development and maturation at the drosophila neuromuscular junction

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