Modulation of synaptic transmission and plasticity by cell adhesion and repulsion molecules

Dityatev, Alexander; Bukalo, Olena; Schachner, Melitta

doi:10.1017/s1740925x09990111

Cited by 79 publications

(58 citation statements)

References 125 publications

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“…The two homologous MDGA proteins, MDGA1 and MDGA2, possess a characteristic domain organization composed of six Ig domains, a fibronectin type III repeat (FNIII), a single meprin/A5 protein/receptor protein tyrosine phosphatase mu (MAM) domain, and a C-terminal GPI anchor (12). Like other Igdomain superfamily members, including neural cell adhesion molecule (NCAM) and L1 cell adhesion molecule (L1-CAM), MDGA proteins may mediate homophilic cell adhesion (13,14). MDGAs are highly expressed in the developing brain (12,15,16).…”

mentioning

confidence: 99%

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Lee

Kim

Lee³

et al. 2012

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

117

139

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The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2-dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...

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mentioning

confidence: 99%

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Lee

Kim

Lee³

et al. 2012

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

117

139

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“…It is thus not surprising that several classes of adhesion molecules have also been identified at the synapse, including proteins of the immunoglobulin superfamily, integrins, neuroligin/neurexins, and ephrin/eph receptors (Gerrow and El-Husseini 2006;Craig and Kang 2007;Dalva et al 2007;Shapiro et al 2007;Dityatev et al 2008;Togashi et al 2009;Woo et al 2009;Zipursky and Sanes 2010). Beyond their role in structural organization and maintenance of the synapse, many of these adhesion molecules play a special role in synaptogenesis and/or in long-term synaptic plasticity.…”

Section: The Synaptic Cleftmentioning

confidence: 99%

Ultrastructure of Synapses in the Mammalian Brain

Harris¹,

Weinberg²

2012

Cold Spring Harbor Perspectives in Biology

342

312

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The morphology and molecular composition of synapses provide the structural basis for synaptic function. This article reviews the electron microscopy of excitatory synapses on dendritic spines, using data from rodent hippocampus, cerebral cortex, and cerebellar cortex. Excitatory synapses have a prominent postsynaptic density, in contrast with inhibitory synapses, which have less dense presynaptic or postsynaptic specializations and are usually found on the cell body or proximal dendritic shaft. Immunogold labeling shows that the presynaptic active zone provides a scaffold for key molecules involved in the release of neurotransmitter, whereas the postsynaptic density contains ligand-gated ionic channels, other receptors, and a complex network of signaling molecules. Delineating the structure and molecular organization of these axospinous synapses represents a crucial step toward understanding the mechanisms that underlie synaptic transmission and the dynamic modulation of neurotransmission associated with short-and long-term synaptic plasticity.

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“…Contactin-1 appears not to be related to synapse development but to synaptic plasticity, and in particular LTD maintenance. 89 Localization of contactin-1 in dendrites, dendritic spine heads, and PSDs in the hippocampus 90 supports its role at the synapse. Lack of Thy-1, an Ig-CAM, 89 blocks LTP.…”

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confidence: 89%

“…89 Localization of contactin-1 in dendrites, dendritic spine heads, and PSDs in the hippocampus 90 supports its role at the synapse. Lack of Thy-1, an Ig-CAM, 89 blocks LTP. 91 Caveolins have been considered to be present only in caveolae and not in noncaveolar membrane rafts.…”

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confidence: 89%

Molecular and structural bases for postsynaptic signal processing: interaction between postsynaptic density and postsynaptic membrane rafts

Suzuki¹,

Yao²

2013

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Postsynaptic membrane rafts (or lipid rafts) (PSRs), together with the postsynaptic density (PSD), are believed to be major sites important for postsynaptic signaling, function, and plasticity. Although the PSD has received much attention and is extensively investigated, PSR roles and their relationship with PSDs are poorly understood. Our recent work has identified PSD-PSR complexes from synaptic membranes of the rat brain and demonstrated specific interactions between them in vitro. Here, we review recent progress in this field, focusing on the molecular identities of the PSR, its biochemical purification, and its potential roles in postsynaptic signaling, function, and plasticity via cross talk with the PSD. We propose that the PSR and PSD are two major postsynaptic signaling domains that interact physiologically, and that PSRs are indispensable to PSD functions. Roles of PSRs in synaptogenesis, growth, and maturation of developing PSDs, and support and regulation of functions and plasticity of mature PSDs are discussed.

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Modulation of synaptic transmission and plasticity by cell adhesion and repulsion molecules

Cited by 79 publications

References 125 publications

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Ultrastructure of Synapses in the Mammalian Brain

Molecular and structural bases for postsynaptic signal processing: interaction between postsynaptic density and postsynaptic membrane rafts

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